moxml 0.1.9 → 0.1.11

data/spec/fixtures/round-trips/niso-jats/pnas_sample.xml

@@ -0,0 +1,3768 @@
+<?xml version="1.0" encoding="UTF-8"?>
+<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.3 20210610//EN" "JATS-journalpublishing1-3.dtd">
+
+<article
+  article-type="research-article"
+  dtd-version="1.3"
+  xml:lang="en"
+  xmlns:mml="http://www.w3.org/1998/Math/MathML"
+  xmlns:xlink="http://www.w3.org/1999/xlink"
+  xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
+  <processing-meta
+    tagset-family="jats"
+    base-tagset="publishing"
+    mathml-version="2.0"
+    table-model="xhtml" />
+  <front>
+    <journal-meta>
+      <journal-id journal-id-type="pmc">pnas</journal-id>
+      <journal-id journal-id-type="pubmed">Proc Natl Acad Sci U S A</journal-id>
+      <journal-id journal-id-type="publisher">PNAS</journal-id>
+      <issn>0027-8424</issn>
+      <publisher>
+        <publisher-name>The National Academy of Sciences</publisher-name>
+      </publisher>
+    </journal-meta>
+    <article-meta>
+      <article-id pub-id-type="publisher-id">181325198</article-id>
+      <article-id pub-id-type="publisher-id">3251</article-id>
+      <article-id pub-id-type="doi">10.1073/pnas.181325198</article-id>
+      <article-id pub-id-type="other">jPNAS.v98.i18.pg10214</article-id>
+      <article-id pub-id-type="pmid">11517319</article-id>
+      <article-version vocab="JAV"
+        vocab-identifier="http://www.niso.org/publications/rp/RP-8-2008.pdf"
+        vocab-term="Version of Record"
+        article-version-type="VoR"
+      >Version of Record</article-version>
+      <article-categories>
+        <subj-group>
+          <subject>Physical Sciences</subject>
+          <subj-group>
+            <subject>Applied Mathematics</subject>
+          </subj-group>
+        </subj-group>
+        <subj-group>
+          <subject>Biological Sciences</subject>
+          <subj-group>
+            <subject>Genetics</subject>
+          </subj-group>
+        </subj-group>
+      </article-categories>
+      <title-group>
+        <article-title>The coreceptor mutation CCR5&#x0394;32 influences the dynamics of HIV
+          epidemics and is selected for by HIV</article-title>
+      </title-group>
+      <contrib-group content-type="authors">
+        <contrib contrib-type="author">
+          <name>
+            <surname>Sullivan</surname>
+            <given-names>Amy D.</given-names>
+          </name>
+          <role degree-contribution="lead"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writer &#8212; original draft"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-original-draft/"
+          >Wrote
+            the original draft</role>
+          <role degree-contribution="lead"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writing &#8212; Review &amp; Editing"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-review-editing/">Led
+            the team for the edit review and did the rewrite</role>
+          <xref ref-type="author-notes" rid="FN150">&#x002A;</xref>
+          <xref ref-type="aff" rid="aff-1" />
+        </contrib>
+        <contrib contrib-type="author">
+          <name>
+            <surname>Wigginton</surname>
+            <given-names>Janis</given-names>
+          </name>
+          <role degree-contribution="lead"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writer &#8212; original draft"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-original-draft/"
+          >Co-wrote
+            Discussion Section for original draft</role>
+          <xref ref-type="aff" rid="aff-1" />
+        </contrib>
+        <contrib contrib-type="author">
+          <name>
+            <surname>Kirschner</surname>
+            <given-names>Denise</given-names>
+          </name>
+          <role degree-contribution="supporting"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writer &#8212; original draft"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-original-draft/"
+          >Co-wrote
+            Model Section for original draft</role>
+          <role degree-contribution="supporting"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writing &#8212; Review &amp; Editing"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-review-editing/">Writing
+            &#8212; Review &amp; Editing</role>
+          <xref ref-type="corresp" rid="FN151">&#x2020;</xref>
+          <xref ref-type="aff" rid="aff-1" />
+        </contrib>
+      </contrib-group>
+      <contrib-group content-type="software">
+        <contrib contrib-type="software">
+          <name>
+            <surname>Krosky</surname>
+            <given-names>Mark</given-names>
+          </name>
+          <role degree-contribution="equal"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Software"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/software/"
+          >Programming
+            and technical assistance</role>
+        </contrib>
+        <contrib contrib-type="software">
+          <name>
+            <surname>Koelle</surname>
+            <given-names>Katia</given-names>
+          </name>
+          <role degree-contribution="equal"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Software"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/software/"
+          >Programming
+            and technical assistance</role>
+        </contrib>
+        <contrib contrib-type="software">
+          <name>
+            <surname>Chung</surname>
+            <given-names>Kevin</given-names>
+          </name>
+          <role degree-contribution="supporting"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Software"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/software/"
+          >Programming
+            and technical assistance</role>
+        </contrib>
+      </contrib-group>
+      <contrib-group content-type="reviewers">
+        <contrib contrib-type="reviewer">
+          <name>
+            <surname>DiRita</surname>
+            <given-names>V. J.</given-names>
+            <prefix>Dr.</prefix>
+          </name>
+          <role degree-contribution="supporting"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writing &#8212; Review &amp; Editing"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-review-editing/"
+          >Helpful
+            comments and discussions</role>
+        </contrib>
+        <contrib contrib-type="reviewer">
+          <name>
+            <surname>Kazanjian</surname>
+            <given-names>P.</given-names>
+            <prefix>Dr.</prefix>
+          </name>
+          <role degree-contribution="supporting"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writing &#8212; Review &amp; Editing"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-review-editing/"
+          >Helpful
+            comments and discussions</role>
+        </contrib>
+        <contrib contrib-type="reviewer">
+          <name>
+            <surname>Blower</surname>
+            <given-names>S. M.</given-names>
+            <prefix>Dr.</prefix>
+          </name>
+          <role degree-contribution="supporting"
+            vocab="CRediT"
+            vocab-identifier="http://credit.niso.org"
+            vocab-term="Writing &#8212; Review &amp; Editing"
+            vocab-term-identifier="http://credit.niso.org/contributor-roles/writing-review-editing/"
+          >Helpful
+            comments and discussions</role>
+        </contrib>
+      </contrib-group>
+      <aff id="aff-1">Department of Microbiology and Immunology, University
+        of Michigan Medical School, Ann Arbor, MI 48109-0620</aff>
+      <author-notes>
+        <fn id="FN150" fn-type="present-address">
+          <p>&#x002A; Present address: Centers for Disease Control and Prevention Epidemiology
+            Program Office, State Branch Oregon Health Division, 800 NE Oregon Street, Suite 772,
+            Portland, OR 97232.</p>
+        </fn>
+        <corresp id="FN151">&#x2020; To whom reprint requests should be addressed. E-mail: <email>
+          kirschne@umich.edu</email>.</corresp>
+        <fn fn-type="com">
+          <p>Communicated by Avner Friedman, University of
+            Minnesota, Minneapolis, MN</p>
+        </fn>
+      </author-notes>
+      <pub-date date-type="pub" publication-format="print"
+        iso-8601-date="2001-08-28">
+        <day>28</day>
+        <month>8</month>
+        <year>2001</year>
+      </pub-date>
+      <pub-date date-type="pub" publication-format="electronic"
+        iso-8601-date="2001-08-21">
+        <day>21</day>
+        <month>8</month>
+        <year>2001</year>
+      </pub-date>
+      <volume>98</volume>
+      <issue>18</issue>
+      <fpage>10214</fpage>
+      <lpage>10219</lpage>
+      <history>
+        <date date-type="received" iso-8601-date="2000-05-30">
+          <day>30</day>
+          <month>5</month>
+          <year>2000</year>
+        </date>
+        <date date-type="accepted" iso-8601-date="2001-06-27">
+          <day>27</day>
+          <month>6</month>
+          <year>2001</year>
+        </date>
+      </history>
+      <permissions>
+        <copyright-statement>Copyright &#x00A9; 2001, The National Academy of Sciences</copyright-statement>
+        <copyright-year>2001</copyright-year>
+      </permissions>
+      <abstract>
+        <p>We explore the impact of a host genetic factor on heterosexual HIV epidemics by using a
+          deterministic mathematical model. A protective allele unequally distributed across
+          populations is exemplified in our models by the 32-bp deletion in the host-cell chemokine
+          receptor CCR5, CCR5&#x0394;32. Individuals homozygous for CCR5&#x0394;32 are protected
+          against HIV infection whereas those heterozygous for CCR5&#x0394;32 have lower pre-AIDS
+          viral loads and delayed progression to AIDS. CCR5&#x0394;32 may limit HIV spread by
+          decreasing the probability of both risk of infection and infectiousness. In this work, we
+          characterize epidemic HIV within three dynamic subpopulations: CCR5&#x002F;CCR5
+          (homozygous, wild type), CCR5&#x002F;CCR5&#x0394;32 (heterozygous), and
+          CCR5&#x0394;32&#x002F;CCR5&#x0394;32 (homozygous, mutant). Our results indicate that
+          prevalence of HIV&#x002F;AIDS is greater in populations lacking the CCR5&#x0394;32 alleles
+          (homozygous wild types only) as compared with populations that include people heterozygous
+          or homozygous for CCR5&#x0394;32. Also, we show that HIV can provide selective pressure
+          for CCR5&#x0394;32, increasing the frequency of this allele.</p>
+      </abstract>
+    </article-meta>
+  </front>
+  <body>
+    <p>Nineteen million people have died of AIDS since the discovery of HIV in the 1980s. In 1999
+      alone, 5.4 million people were newly infected with HIV (ref. <xref ref-type="bibr" rid="B1">1</xref>
+      and <ext-link ext-link-type="url" xmlns:xlink="http://www.w3.org/1999/xlink"
+        xlink:href="http://www.unaids.org/epidemicupdate/report/Epireport.html">
+      http://www.unaids.org/epidemicupdate/report/Epireport.html</ext-link>). (For brevity, HIV-1 is
+      referred to as HIV in this paper.) Sub-Saharan Africa has been hardest hit, with more than
+      20&#x0025; of the general population HIV-positive in some countries (<xref ref-type="bibr"
+        rid="B2">2</xref>, <xref ref-type="bibr" rid="B3">3</xref>). In comparison, heterosexual
+      epidemics in developed, market-economy countries have not reached such severe levels. Factors
+      contributing to the severity of the epidemic in economically developing countries abound,
+      including economic, health, and social differences such as high levels of sexually transmitted
+      diseases and a lack of prevention programs. However, the staggering rate at which the epidemic
+      has spread in sub-Saharan Africa has not been adequately explained. The rate and severity of
+      this epidemic also could indicate a greater underlying susceptibility to HIV attributable not
+      only to sexually transmitted disease, economics, etc., but also to other more ubiquitous
+      factors such as host genetics (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr"
+        rid="B5">5</xref>).</p>
+    <p>To exemplify the contribution of such a host genetic factor to HIV prevalence trends, we
+      consider a well-characterized 32-bp deletion in the host-cell chemokine receptor CCR5,
+      CCR5&#x0394;32. When HIV binds to host cells, it uses the CD4 receptor on the surface of host
+      immune cells together with a coreceptor, mainly the CCR5 and CXCR4 chemokine receptors (<xref
+        ref-type="bibr" rid="B6">6</xref>). Homozygous mutations for this 32-bp deletion offer
+      almost complete protection from HIV infection, and heterozygous mutations are associated with
+      lower pre-AIDS viral loads and delayed progression to AIDS (<xref ref-type="bibr" rid="B7">7</xref>
+      &#x2013;<xref ref-type="bibr" rid="B14">14</xref>). CCR5&#x0394;32 generally is found in
+      populations of European descent, with allelic frequencies ranging from 0 to 0.29 (<xref
+        ref-type="bibr" rid="B13">13</xref>). African and Asian populations studied outside the
+      United States or Europe appear to lack the CCR5&#x0394;32 allele, with an allelic frequency of
+      almost zero (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B13">13</xref>).
+      Thus, to understand the effects of a protective allele, we use a mathematical model to track
+      prevalence of HIV in populations with or without CCR5&#x0394;32 heterozygous and homozygous
+      people and also to follow the CCR5&#x0394;32 allelic frequency.</p>
+    <p>We hypothesize that CCR5&#x0394;32 limits epidemic HIV by decreasing infection rates, and we
+      evaluate the relative contributions to this by the probability of infection and duration of
+      infectivity. To capture HIV infection as a chronic infectious disease together with vertical
+      transmission occurring in untreated mothers, we model a dynamic population (i.e., populations
+      that vary in growth rates because of fluctuations in birth or death rates) based on realistic
+      demographic characteristics (<xref ref-type="bibr" rid="B18">18</xref>). This scenario also
+      allows tracking of the allelic frequencies over time. This work considers how a specific host
+      genetic factor affecting HIV infectivity and viremia at the individual level might influence
+      the epidemic in a dynamic population and how HIV exerts selective pressure, altering the
+      frequency of this mutant allele.</p>
+    <p>CCR5 is a host-cell chemokine receptor, which is also used as a coreceptor by R5 strains of
+      HIV that are generally acquired during sexual transmission (<xref ref-type="bibr" rid="B6">6</xref>
+      , <xref ref-type="bibr" rid="B19">19</xref>&#x2013;<xref ref-type="bibr" rid="B25">25</xref>).
+      As infection progresses to AIDS the virus expands its repertoire of potential coreceptors to
+      include other CC-family and CXC-family receptors in roughly 50&#x0025; of patients (<xref
+        ref-type="bibr" rid="B19">19</xref>, <xref ref-type="bibr" rid="B26">26</xref>, <xref
+        ref-type="bibr" rid="B27">27</xref>). CCR5&#x0394;32 was identified in HIV-resistant people
+      (<xref ref-type="bibr" rid="B28">28</xref>). Benefits to individuals from the mutation in this
+      allele are as follows. Persons homozygous for the CCR5&#x0394;32 mutation are almost
+      nonexistent in HIV-infected populations (<xref ref-type="bibr" rid="B11">11</xref>, <xref
+        ref-type="bibr" rid="B12">12</xref>) (see ref. <xref ref-type="bibr" rid="B13">13</xref> for
+      review). Persons heterozygous for the mutant allele (CCR5 W/&#x0394;32) tend to have lower
+      pre-AIDS viral loads. Aside from the beneficial effects that lower viral loads may have for
+      individuals, there is also an altruistic effect, as transmission rates are reduced for
+      individuals with low viral loads (as compared with, for example, AZT and other studies; ref. <xref
+        ref-type="bibr" rid="B29">29</xref>). Finally, individuals heterozygous for the mutant
+      allele (CCR5 W/&#x0394;32) also have a slower progression to AIDS than those homozygous for
+      the wild-type allele (CCR5 W/W) (<xref ref-type="bibr" rid="B7">7</xref>&#x2013;<xref
+        ref-type="bibr" rid="B10">10</xref>), remaining in the population 2 years longer, on
+      average. Interestingly, the dearth of information on HIV disease progression in people
+      homozygous for the CCR5&#x0394;32 allele (CCR5 &#x0394;32/&#x0394;32) stems from the rarity of
+      HIV infection in this group (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr"
+        rid="B12">12</xref>, <xref ref-type="bibr" rid="B28">28</xref>). However, in case reports of
+      HIV-infected CCR5 &#x0394;32/&#x0394;32 homozygotes, a rapid decline in CD4<sup>&#x002B;</sup>
+      T cells and a high viremia are observed, likely because of initial infection with a more
+      aggressive viral strain (such as X4 or R5X4) (<xref ref-type="bibr" rid="B30">30</xref>).</p>
+    <sec>
+      <title>The Model</title>
+      <p>Because we are most concerned with understanding the severity of the epidemic in developing
+        countries where the majority of infection is heterosexual, we consider a purely heterosexual
+        model. To model the effects of the allele in the population, we examine the rate of HIV
+        spread by using an enhanced susceptible-infected-AIDS model of epidemic HIV (for review see
+        ref. <xref ref-type="bibr" rid="B31">31</xref>). Our model compares two population
+        scenarios: a CCR5 wild-type population and one with CCR5&#x0394;32 heterozygotes and
+        homozygotes in addition to the wild type. To model the scenario where there are only
+        wild-type individuals present in the population (i.e., CCR5 W/W), we track the sexually
+        active susceptibles at time <italic>t</italic> &#x005B;<italic>S<sub>i,j</sub>
+        </italic>
+        (<italic>t</italic>)&#x005D;, where <italic>i</italic> = 1 refers to genotype (CCR5 W/W only
+        in this case) and <italic>j</italic> is either the male or female subpopulation. We also
+        track those who are HIV-positive at time <italic>t</italic> not yet having AIDS in <italic>I<sub>
+        i,j,k</sub>
+        </italic>(<italic>t</italic>) where <italic>k</italic> refers to stage of
+        HIV infection &#x005B;primary (<italic>A</italic>) or asymptomatic (<italic>B</italic>)&#x005D;.
+        The total number of individuals with AIDS at time <italic>t</italic> are tracked in <italic>
+        A</italic>(<italic>t</italic>). The source population are children, &#x03C7;<sub>
+          <italic>i,j</italic>
+        </sub>(<italic>t</italic>), who mature into the sexually
+        active population at time <italic>t</italic> (Fig. <xref ref-type="fig" rid="F1">1</xref>,
+        Table <xref ref-type="table" rid="T1">1</xref>). We compare the model of a population
+        lacking the CCR5&#x0394;32 allele to a demographically similar population with a high
+        frequency of the allele. When genetic heterogeneity is included, male and female
+        subpopulations are each further divided into three distinct genotypic groups, yielding six
+        susceptible subpopulations, &#x005B;<italic>S<sub>i,j</sub>
+        </italic>(<italic>t</italic>),
+        where <italic>i</italic> ranges from 1 to 3, where 1 = CCR5W/W; 2 = CCR5 W/&#x0394;32; 3 =
+        CCR5 &#x0394;32/&#x0394;32&#x005D;. The infected classes, <italic>I<sub>i,j,k</sub>
+        </italic>
+        (<italic>t</italic>), also increase in number to account for these new genotype
+        compartments. In both settings we assume there is no treatment available and no knowledge of
+        HIV status by people in the early acute and middle asymptomatic stages (both conditions
+        exist in much of sub-Saharan Africa). In addition, we assume that sexual mixing in the
+        population occurs randomly with respect to genotype and HIV disease status, all HIV-infected
+        people eventually progress to AIDS, and no barrier contraceptives are used. These last
+        assumptions reflect both economic and social conditions. </p>
+      <fig id="F1">
+        <label>Figure 1</label>
+        <caption>
+          <p>A schematic representation of the basic compartmental HIV epidemic model. The
+            criss-cross lines indicate the sexual mixing between different compartments. Each of
+            these interactions has a positive probability of taking place; they also incorporate
+            individual rates of transmission indicated as &#x03BB;, but in full notation is &#x03BB;<sub>
+              <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>,<italic>&#xEA50;</italic>&#x2192;<italic>
+            i</italic>,<italic>j</italic>,</sub> where <italic>i</italic>,<italic>j</italic>,<italic>
+            k</italic> is the phenotype of the infected partner and <italic>&#x00EE;</italic>,<italic>
+            &#xEB30;</italic> is the phenotype of the susceptible partner. Also shown are the
+            different rates of disease progression, &#x03B3;<sub>
+              <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+            </sub>, that vary
+            according to genotype, gender, and stage. Thus, the interactions between different
+            genotypes, genders, and stages are associated with a unique probability of HIV
+            infection. M, male; F, female.</p>
+        </caption>
+        <graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="pq1813251001">
+        </graphic>
+      </fig>
+      <table-wrap id="T1">
+        <label>Table 1</label>
+        <caption>
+          <p>Children's genotype</p>
+        </caption>
+        <table>
+          <tr>
+            <th>Parents</th>
+            <th colspan="4">Mother</th>
+          </tr>
+          <tr>
+            <td colspan="5">
+              <hr />
+            </td>
+          </tr>
+          <tr>
+            <td>Father</td>
+            <td />
+            <td>W&#x002F;W</td>
+            <td>W&#x002F;&#x0394;32</td>
+            <td>&#x0394;32&#x002F;&#x0394;32</td>
+          </tr>
+          <tr>
+            <td />
+            <td>W&#x002F;W</td>
+            <td>&#x03C7;<sub>1,<italic>j</italic>
+              </sub>1,<italic>j</italic>
+            </td>
+            <td>&#x03C7;<sub>1,<italic>j</italic>
+              </sub>1,<italic>j</italic>, &#x03C7;<sub>
+              2,<italic>j</italic>
+              </sub>2,<italic>j</italic>
+            </td>
+            <td>&#x03C7;<sub>2,<italic>j</italic>
+              </sub>2,<italic>j</italic>
+            </td>
+          </tr>
+          <tr>
+            <td />
+            <td>W&#x002F;&#x0394;32</td>
+            <td>&#x03C7;<sub>1,<italic>j</italic>
+              </sub>1,<italic>j</italic>, &#x03C7;<sub>
+              2,<italic>j</italic>
+              </sub>2,<italic>j</italic>
+            </td>
+            <td>&#x03C7;<sub>1,<italic>j</italic>
+              </sub>1,<italic>j</italic>, &#x03C7;<sub>
+              2,<italic>j</italic>
+              </sub>2,<italic>j</italic>, &#x03C7;<sub>3,<italic>j</italic>
+              </sub>
+              3,<italic>j</italic>
+            </td>
+            <td>&#x03C7;<sub>2,<italic>j</italic>
+              </sub>2,<italic>j</italic>, &#x03C7;<sub>
+              3,<italic>j</italic>
+              </sub>3,<italic>j</italic>
+            </td>
+          </tr>
+          <tr>
+            <td />
+            <td>&#x0394;32&#x002F;&#x0394;32</td>
+            <td>&#x03C7;<sub>2,<italic>j</italic>
+              </sub>2,<italic>j</italic>
+            </td>
+            <td>&#x03C7;<sub>2,<italic>j</italic>
+              </sub>2,<italic>j</italic>, &#x03C7;<sub>
+              3,<italic>j</italic>
+              </sub>3,<italic>j</italic>
+            </td>
+            <td>&#x03C7;<sub>3,<italic>j</italic>
+              </sub>3,<italic>j</italic>
+            </td>
+          </tr>
+        </table>
+        <table-wrap-foot>
+          <fn>
+            <p>&#x03C7;<sub>1,<italic>j</italic>
+              </sub>1,<italic>j</italic> = wild-type
+              children; (W&#x002F;W); &#x03C7;<sub>2,<italic>j</italic>
+              </sub>2,<italic>
+              j</italic> = heterozygous children (W&#x002F;&#x0394;32); &#x03C7;<sub>3,<italic>j</italic>
+              </sub>
+              3,<italic>j</italic> = homozygous children (&#x0394;32&#x002F;&#x0394;32) of gender <italic>
+              j</italic>. Children's genotypes are determined by using Mendelian inheritance
+              patterns.</p>
+          </fn>
+        </table-wrap-foot>
+      </table-wrap>
+      <sec>
+        <title>Parameter Estimates for the Model.</title>
+        <p>Estimates for rates that govern the interactions depicted in Fig. <xref ref-type="fig"
+            rid="F1">1</xref> were derived from the extensive literature on HIV. Our parameters and
+          their estimates are summarized in Tables <xref ref-type="table" rid="T2">2</xref>&#x2013;<xref
+            ref-type="table" rid="T4">4</xref>. The general form of the equations describing the
+          rates of transition between population classes as depicted in Fig. <xref ref-type="fig"
+            rid="F1">1</xref> are summarized as follows: <disp-formula id="E1">
+            <tex-math id="M1">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          \frac{dS_{i,j}(t)}{dt}={\chi}_{i,j}(t)-{\mu}_{j}S_{i,j}(t)-{\lambda}_{\hat {\imath},\hat
+          {},\hat {k}{\rightarrow}i,j}S_{i,j}(t), $$ \end{document} </tex-math>
+          </disp-formula>
+<disp-formula
+            id="E2">
+            <tex-math id="M2">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          \hspace{1em}\hspace{1em}\hspace{.167em}\frac{dI_{i,j,A}(t)}{dt}={\lambda}_{\hat
+          {\imath},\hat {},\hat
+          {k}{\rightarrow}i,j}S_{i,j}(t)-{\mu}_{j}I_{i,j,A}(t)-{\gamma}_{i,j,A}I_{i,j,A}(t), $$
+          \end{document} </tex-math>
+          </disp-formula>
+<disp-formula id="E3">
+            <tex-math id="M3">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          \frac{dI_{i,j,B}(t)}{dt}={\gamma}_{i,j,A}I_{i,j,A}(t)-{\mu}_{j}I_{i,j,B}(t)-{\gamma}_{i,j,B}I_{i,j,B}(t),
+          $$ \end{document} </tex-math>
+          </disp-formula>
+<disp-formula id="E4">
+            <tex-math id="M4">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          \frac{dA(t)}{dt}={\gamma}_{i,j,B} \left( { \,\substack{ ^{3} \\ {\sum} \\ _{i=1} }\,
+          }I_{i,F,B}(t)+I_{i,M,B}(t) \right) -{\mu}_{A}A(t)-{\delta}A(t), $$ \end{document} </tex-math>
+          </disp-formula>
+          where, in addition to previously defined populations and rates (with <italic>i</italic>
+          equals genotype, <italic>j</italic> equals gender, and <italic>k</italic> equals stage of
+          infection, either <italic>A</italic> or <italic>B</italic>), &#x03BC;<sub>
+            <italic>j</italic>
+          </sub>, represents the non-AIDS (natural) death rate for
+          males and females respectively, and &#x03BC;<sub>A</sub> is estimated by the average
+          (&#x03BC;<sub>F</sub> &#x002B; &#x03BC;<sub>M</sub>/2). This approximation allows us to
+          simplify the model (only one AIDS compartment) without compromising the results, as most
+          people with AIDS die of AIDS (&#x03B4;<sub>AIDS</sub>) and very few of other causes
+          (&#x03BC;<sub>A</sub>). These estimates include values that affect infectivity (&#x03BB;<sub>
+            <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>,<italic>&#xEA50;</italic>&#x2192;<italic>
+          i</italic>,<italic>j</italic>
+          </sub>), transmission (&#x03B2;<sub>
+            <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>,<italic>&#xEA50;</italic>&#x2192;<italic>
+          i</italic>,<italic>j</italic>
+          </sub>), and disease progression (&#x03B3;<sub>
+            <italic>i</italic>
+          </sub>
+<sub>,</sub>
+<sub>
+            <italic>j</italic>
+          </sub>
+<sub>,</sub>
+<sub>
+            <italic>k</italic>
+          </sub>) where the <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>
+          ,<italic>&#xEA50;</italic> notation represents the genotype, gender, and stage of
+          infection of the infected partner, and <italic>j</italic> &#x2260; <italic>&#xEB30;</italic>
+          . </p>
+        <table-wrap id="T2">
+          <label>Table 2</label>
+          <caption>
+            <p>Transmission probabilities</p>
+          </caption>
+          <table>
+            <tr>
+              <th rowspan="3">HIV-infected partner (&#x00EE;&#x0131;&#x0131;&#x005E;&#x005E;,
+                &#xEB30;&#xE2D4;&#xE2D4;&#x005E;&#x005E;, &#xEA50;<italic>k</italic>
+<italic>k</italic>
+                &#x005E;&#x005E;)</th>
+              <th colspan="4">Susceptible partner (<italic>i</italic>, <italic>j</italic>)</th>
+            </tr>
+            <tr>
+              <td colspan="4">
+                <hr />
+              </td>
+            </tr>
+            <tr>
+              <th>(&#xEB30;&#xE2D4;&#xE2D4;&#x005E;&#x005E; to <italic>j</italic>)</th>
+              <th>W&#x002F;W</th>
+              <th>W&#x002F;&#x0394;32</th>
+              <th>&#x0394;32&#x002F;&#x0394;32 </th>
+            </tr>
+            <tr>
+              <td colspan="5">
+                <hr />
+              </td>
+            </tr>
+            <tr>
+              <td>Acute&#x002F;primary</td>
+            </tr>
+            <tr>
+              <td>&#x2003;W&#x002F;W or &#x0394;32&#x002F;&#x0394;32</td>
+              <td>M to F</td>
+              <td>0.040</td>
+              <td>0.040</td>
+              <td>0.00040 </td>
+            </tr>
+            <tr>
+              <td />
+              <td>F to M</td>
+              <td>0.020</td>
+              <td>0.020</td>
+              <td>0.00020 </td>
+            </tr>
+            <tr>
+              <td>&#x2003;W&#x002F;&#x0394;32</td>
+              <td>M to F</td>
+              <td>0.030</td>
+              <td>0.030</td>
+              <td>0.00030 </td>
+            </tr>
+            <tr>
+              <td />
+              <td>F to M</td>
+              <td>0.015</td>
+              <td>0.015</td>
+              <td>0.00015 </td>
+            </tr>
+            <tr>
+              <td>Asymptomatic </td>
+            </tr>
+            <tr>
+              <td>&#x2003;W&#x002F;W or &#x0394;32&#x002F;&#x0394;32</td>
+              <td>M to F</td>
+              <td>0.0010</td>
+              <td>0.0010</td>
+              <td>10 &#x00D7; 10<sup>&#x2212;6</sup>
+              </td>
+            </tr>
+            <tr>
+              <td />
+              <td>F to M</td>
+              <td>0.0005</td>
+              <td>0.0005</td>
+              <td>5 &#x00D7; 10<sup>&#x2212;6</sup>
+              </td>
+            </tr>
+            <tr>
+              <td>&#x2003;W&#x002F;&#x0394;32</td>
+              <td>M to F</td>
+              <td>0.0005</td>
+              <td>0.0005</td>
+              <td>5 &#x00D7; 10<sup>&#x2212;6</sup>
+              </td>
+            </tr>
+            <tr>
+              <td />
+              <td>F to M</td>
+              <td>0.00025</td>
+              <td>0.00025</td>
+              <td>2.5 &#x00D7; 10<sup>&#x2212;6</sup>
+              </td>
+            </tr>
+          </table>
+          <table-wrap-foot>
+            <fn>
+              <p>Listed are the different transmission probabilities (&#x03B2;<sub>
+                &#x00EE;&#x0131;&#x0131;&#x005E;&#x005E;,&#xEB30;&#xE2D4;&#xE2D4;&#x005E;&#x005E;,&#xEA50;<italic>
+                k</italic>
+<italic>k</italic>&#x005E;&#x005E;&#x2192;<italic>i</italic>,<italic>j</italic>
+                </sub>)
+                for random sexual mixing between persons where <italic>i</italic>, <italic>j</italic>
+                , <italic>k</italic> is the phenotype of the infected partner and <italic>i</italic>
+                , <italic>j</italic> is the phenotype of the susceptible partner. M, male; F,
+                female.</p>
+            </fn>
+          </table-wrap-foot>
+        </table-wrap>
+        <table-wrap id="T3">
+          <label>Table 3</label>
+          <caption>
+            <p>Progression rates</p>
+          </caption>
+          <table>
+            <tr>
+              <th>Genotype</th>
+              <th>Disease stage</th>
+              <th>Males&#x002F;females </th>
+            </tr>
+            <tr>
+              <td colspan="3">
+                <hr />
+              </td>
+            </tr>
+            <tr>
+              <td>W&#x002F;W</td>
+              <td>A</td>
+              <td>3.5</td>
+            </tr>
+            <tr>
+              <td />
+              <td>B</td>
+              <td>0.16667 </td>
+            </tr>
+            <tr>
+              <td>W&#x002F;&#x0394;32</td>
+              <td>A</td>
+              <td>3.5 </td>
+            </tr>
+            <tr>
+              <td />
+              <td>B</td>
+              <td>0.125</td>
+            </tr>
+            <tr>
+              <td>&#x0394;32&#x002F;&#x0394;32</td>
+              <td>A</td>
+              <td>3.5 </td>
+            </tr>
+            <tr>
+              <td />
+              <td>B</td>
+              <td>0.16667</td>
+            </tr>
+          </table>
+          <table-wrap-foot>
+            <fn>
+              <p>Shown are the rates of progression, &#x03B3;<sub>
+                  <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+                </sub>
+<italic>
+                i</italic>,<italic>j</italic>,<italic>k</italic> reflecting the different rates at
+                which persons progress through different stages of disease by genotype, gender, and
+                disease stage.</p>
+            </fn>
+          </table-wrap-foot>
+        </table-wrap>
+        <table-wrap id="T4">
+          <label>Table 4</label>
+          <caption>
+            <p>Parameter values</p>
+          </caption>
+          <table>
+            <tr>
+              <th>Parameter</th>
+              <th>Definition</th>
+              <th>Value</th>
+            </tr>
+            <tr>
+              <td colspan="3">
+                <hr />
+              </td>
+            </tr>
+            <tr>
+              <td>&#x03BC;<sub>
+                  <italic>F</italic>
+                </sub>
+<italic>F</italic>, &#x03BC;<sub>
+                  <italic>M</italic>
+                </sub>
+<italic>M</italic>
+              </td>
+              <td align="left">All-cause mortality for adult females (males)</td>
+              <td align="left">0.015 (0.016) per year</td>
+            </tr>
+            <tr>
+              <td>&#x03BC;<sub>&#x03C7;</sub>&#x03C7;</td>
+              <td align="left">All-cause childhood mortality (&#x003C;15 years of age)</td>
+              <td align="left">0.01 per year</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>B</italic>
+                <sub>
+                  <italic>r</italic>
+                </sub>
+                <italic>r</italic>
+              </td>
+              <td align="left">Birthrate</td>
+              <td align="left">0.25 per woman per year</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>SA</italic>
+                <sub>
+                  <italic>F</italic>
+                </sub>
+                <italic>F</italic>
+              </td>
+              <td align="left">Percent females acquiring new partners (sexual activity)</td>
+              <td align="left">10&#x0025;</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>SA</italic>
+                <sub>
+                  <italic>M</italic>
+                </sub>
+                <italic>M</italic>
+              </td>
+              <td align="left">Percent males acquiring new partners (sexual activity)</td>
+              <td align="left">25&#x0025;</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>m</italic>
+<sub>
+                  <italic>F</italic>
+                </sub>
+<italic>F</italic>(&#x03C2;<inline-formula>
+                  <tex-math id="M5">\documentclass[12pt]{minimal} \usepackage{wasysym}
+                \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+                \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+                \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+                &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+                \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+                {\mathrm{_{{F}}^{{2}}}} $$ \end{document} </tex-math>
+                </inline-formula>
+                )</td>
+              <td align="left">Mean (variance) no. of new partners for females</td>
+              <td align="left">1.8 (1.2) per year</td>
+            </tr>
+            <tr>
+              <td>&#x03C2;<inline-formula>
+                  <tex-math id="M6">\documentclass[12pt]{minimal} \usepackage{wasysym}
+                \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+                \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+                \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+                &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+                \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+                {\mathrm{_{{M}}^{{2}}}} $$ \end{document} </tex-math>
+                </inline-formula>
+              </td>
+              <td align="left">Variance in no. of new partners for males</td>
+              <td align="left">5.5 per year </td>
+            </tr>
+            <tr>
+              <td>1 &#x2212; <italic>p</italic>
+<sub>
+                  <italic>v</italic>
+                </sub>
+<italic>v</italic>
+              </td>
+              <td align="left">Probability of vertical transmission</td>
+              <td align="left">0.30 per birth</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>I</italic>
+<sub>
+                  <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+                </sub>
+<italic>
+                i</italic>,<italic>j</italic>,<italic>k</italic>(0)</td>
+              <td align="left">Initial total population HIV-positive</td>
+              <td align="left">0.50&#x0025; </td>
+            </tr>
+            <tr>
+              <td>&#x03C7;<sub>
+                  <italic>i</italic>,<italic>j</italic>
+                </sub>
+<italic>i</italic>,<italic>
+                j</italic>(0)</td>
+              <td align="left">Initial total children in population (&#x003C;15 years of age)</td>
+              <td align="left">45&#x0025;</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>W</italic>&#x002F;<italic>W</italic> (0)</td>
+              <td align="left">Initial total wild types (<italic>W</italic>&#x002F;<italic>W</italic>)
+                in population</td>
+              <td align="left">80&#x0025; </td>
+            </tr>
+            <tr>
+              <td>
+                <italic>W</italic>&#x002F;&#x0394;32(0)</td>
+              <td align="left">Initial total heterozygotes (<italic>W</italic>&#x002F;&#x0394;32) in
+                population</td>
+              <td align="left">19&#x0025;</td>
+            </tr>
+            <tr>
+              <td>&#x0394;32&#x002F;&#x0394;32(0)</td>
+              <td align="left">Initial total homozygotes (&#x0394;32&#x002F;&#x0394;32) in
+                population</td>
+              <td align="left">1&#x0025;</td>
+            </tr>
+            <tr>
+              <td>
+                <italic>r</italic>
+<sub>
+                  <italic>M</italic>
+                </sub>
+<italic>M</italic>(<italic>r</italic>
+<sub>
+                  <italic>F</italic>
+                </sub>
+<italic>F</italic>)</td>
+              <td align="left">Initial percent males (females) in total population</td>
+              <td align="left">49&#x0025; (51&#x0025;)</td>
+            </tr>
+            <tr>
+              <td>&#x03D5;<sub>
+                  <italic>F</italic>
+                </sub>
+<italic>F</italic>, &#x03D5;<sub>
+                  <italic>M</italic>
+                </sub>
+<italic>M</italic>
+              </td>
+              <td align="left">Number of sexual contacts a female (male) has</td>
+              <td align="left">30 (24) per partner</td>
+            </tr>
+            <tr>
+              <td>&#x025B;<sub>
+                  <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+                </sub>
+<italic>
+                i</italic>,<italic>j</italic>,<italic>k</italic>
+              </td>
+              <td align="left">&#x0025; effect of mutation on transmission rates (see Table <xref
+                  ref-type="table" rid="T2">2</xref>)</td>
+              <td align="left">0 &#x003C; &#x025B;<sub>
+                  <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+                </sub>
+<italic>
+                i</italic>,<italic>j</italic>,<italic>k</italic> &#x003C; 1</td>
+            </tr>
+            <tr>
+              <td>&#x03B4;</td>
+              <td align="left">Death rate for AIDS population</td>
+              <td align="left">1.0 per year </td>
+            </tr>
+            <tr>
+              <td>
+                <italic>q</italic>
+              </td>
+              <td align="left">Allelic frequency of &#x0394;32 allele</td>
+              <td align="left">0.105573</td>
+            </tr>
+          </table>
+          <table-wrap-foot>
+            <fn>
+              <p>Shown are the parameter values for parameters other than the transmission
+                probabilities (Table <xref ref-type="table" rid="T2">2</xref>) and the progression
+                rates (Table <xref ref-type="table" rid="T3">3</xref>). Each were estimated from
+                data as described in text.</p>
+            </fn>
+          </table-wrap-foot>
+        </table-wrap>
+        <p>The effects of the CCR5 W/&#x0394;32 and CCR5 &#x0394;32/&#x0394;32 genotypes are
+          included in our model through both the per-capita probabilities of infection, &#x03BB;<sub>
+            <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>,<italic>&#xEA50;</italic>&#x2192;<italic>
+          i</italic>,<italic>j</italic>
+          </sub>, and the progression rates, &#x03B3;<sub>
+            <italic>i</italic>
+          </sub>
+<sub>,</sub>
+<sub>
+            <italic>j</italic>
+          </sub>
+<sub>,</sub>
+<sub>
+            <italic>k</italic>
+          </sub>. The infectivity coefficients, &#x03BB;<sub>
+            <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>,<italic>&#xEA50;</italic>&#x2192;<italic>
+          i</italic>,<italic>j</italic>
+          </sub>, are calculated for each population subgroup
+          based on the following: likelihood of HIV transmission in a sexual encounter between a
+          susceptible and an infected (&#x03B2;<sub>&#x00EE;&#x0131;&#x0131;&#x005E;&#x005E;,<italic>
+          j</italic>,&#xEA50;<italic>k</italic>
+<italic>k</italic>&#x005E;&#x005E;&#x2192;<italic>i</italic>
+          ,<italic>j</italic>
+          </sub>) person; formation of new partnerships (<italic>c</italic>
+<sub>
+            <italic>j</italic>
+          </sub>
+<italic>j</italic>); number of contacts in a given
+          partnership (&#x03D5;<sub>
+            <italic>j</italic>
+          </sub>); and probability of encountering an infected
+          individual (<italic>I</italic>
+<sub>
+            <italic>&#x00EE;</italic>,<italic>&#xEB30;</italic>,<italic>&#xEA50;</italic>
+          </sub>
+          /<italic>N</italic>
+<sub>
+            <italic>&#xEB30;</italic>
+          </sub>). The formula representing this probability of
+          infection is <disp-formula>
+            <tex-math id="M7">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$ {\lambda}_{\hat
+          {i},\hat {j},\hat {k}{\rightarrow}i,j}=\frac{C_{j}{\cdot}{\phi}_{j}}{N_{\hat
+          {j}}}\hspace{.167em} \left[ { \,\substack{ \\ {\sum} \\ _{\hat {i},\hat {k}} }\,
+          }{\beta}_{\hat {i},\hat {j},\hat {k}{\rightarrow}i,j}{\cdot}I_{\hat {i},\hat {j},\hat {k}}
+          \right] , $$ \end{document} </tex-math>
+          </disp-formula> where <italic>j</italic>
+          &#x2260; <italic>&#xEB30;</italic> is either male or female. <italic>N</italic>
+<sub>
+            <italic>&#xEB30;</italic>
+          </sub> represents the total population of gender <italic>
+          &#xEB30;</italic> (this does not include those with AIDS in the simulations).</p>
+        <p>The average rate of partner acquisition, <italic>c<sub>j</sub>
+          </italic>,
+          includes the mean plus the variance to mean ratio of the relevant distribution of
+          partner-change rates to capture the small number of high-risk people: <italic>c<sub>j</sub>
+          </italic>
+          = <italic>m<sub>j</sub>
+          </italic> &#x002B; (&#x03C2;<inline-formula>
+            <tex-math id="M8">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          {\mathrm{_{{\mathit{j}}}^{2}}} $$ \end{document} </tex-math>
+          </inline-formula>/<italic>
+          m</italic>
+<sub>j</sub>) where the mean (<italic>m<sub>j</sub>
+          </italic>) and
+          variance (&#x03C2;<inline-formula>
+            <tex-math id="M9">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          {\mathrm{_{{\mathit{j}}}^{2}}} $$ \end{document} </tex-math>
+          </inline-formula>)
+          are annual figures for new partnerships only (<xref ref-type="bibr" rid="B32">32</xref>).
+          These means are estimated from Ugandan data for the number of heterosexual partners in the
+          past year (<xref ref-type="bibr" rid="B33">33</xref>) and the number of nonregular
+          heterosexual partners (i.e., spouses or long-term partners) in the past year (<xref
+            ref-type="bibr" rid="B34">34</xref>). In these sexual activity surveys, men invariably
+          have more new partnerships; thus, we assumed that they would have fewer average contacts
+          per partnership than women (a higher rate of new partner acquisition means fewer sexual
+          contacts with a given partner; ref. <xref ref-type="bibr" rid="B35">35</xref>). To
+          incorporate this assumption in our model, the male contacts/partnership, &#x03D5;<sub>
+            <italic>M</italic>
+          </sub>, was reduced by 20&#x0025;. In a given population,
+          the numbers of heterosexual interactions must equate between males and females. The
+          balancing equation applied here is <italic>SA</italic>
+<sub>F</sub>&#x00B7;<italic>m</italic>
+<sub>
+          F</sub>&#x00B7;<italic>N</italic>
+<sub>F</sub> = <italic>SA</italic>
+<sub>M</sub>&#x00B7;<italic>
+          m</italic>
+<sub>M</sub>&#x00B7;<italic>N</italic>
+<sub>M</sub>, where <italic>SA<sub>j</sub>
+          </italic>
+          are the percent sexually active and <italic>N<sub>j</sub>
+          </italic> are the total
+          in the populations for gender <italic>j</italic>. To specify changes in partner
+          acquisition, we apply a male flexibility mechanism, holding the female rate of acquisition
+          constant and allowing the male rates to vary (<xref ref-type="bibr" rid="B36">36</xref>, <xref
+            ref-type="bibr" rid="B37">37</xref>).</p>
+        <sec>
+          <title>Transmission probabilities.</title>
+          <p>The effect of a genetic factor in a model of HIV transmission can be included by
+            reducing the transmission coefficient. The probabilities of transmission per contact
+            with an infected partner, &#x03B2;<sub>
+            &#x00EE;&#x0131;&#x0131;&#x005E;&#x005E;,&#xEB30;&#xE2D4;&#xE2D4;&#x005E;&#x005E;,&#xEA50;<italic>
+            k</italic>
+<italic>k</italic>&#x005E;&#x005E;&#x2192;<italic>i</italic>,<italic>j</italic>
+            </sub>,
+            have been estimated in the literature (see ref. <xref ref-type="bibr" rid="B38">38</xref>
+            for estimates in minimally treated groups). We want to capture a decreased risk in
+            transmission based on genotype (ref. <xref ref-type="bibr" rid="B39">39</xref>, Table <xref
+              ref-type="table" rid="T2">2</xref>). No studies have directly evaluated differences in
+            infectivity between HIV-infected CCR5 W/&#x0394;32 heterozygotes and HIV-infected CCR5
+            wild types. Thus, we base estimates for reduced transmission on studies of groups with
+            various HIV serum viral loads (<xref ref-type="bibr" rid="B40">40</xref>), HTLV-I/II
+            viral loads (<xref ref-type="bibr" rid="B41">41</xref>), and a study of the effect of
+            AZT treatment on transmission (<xref ref-type="bibr" rid="B29">29</xref>). We decrease
+            transmission probabilities for infecting CCR5&#x0394;32/&#x0394;32 persons by 100-fold
+            to reflect the rarity of infections in these persons. However, we assume that infected
+            CCR5&#x0394;32/&#x0394;32 homozygotes can infect susceptibles at a rate similar to
+            CCR5W/W homozygotes, as the former generally have high viremias (ref. <xref
+              ref-type="bibr" rid="B30">30</xref>, Table <xref ref-type="table" rid="T2">2</xref>).
+            We also assume that male-to-female transmission is twice as efficient as female-to-male
+            transmission (up to a 9-fold difference has been reported; ref. <xref ref-type="bibr"
+              rid="B42">42</xref>) (ref. <xref ref-type="bibr" rid="B43">43</xref>, Table <xref
+              ref-type="table" rid="T2">2</xref>).</p>
+          <p>Given the assumption of no treatment, the high burden of disease in people with AIDS is
+            assumed to greatly limit their sexual activity. Our initial model excludes people with
+            AIDS from the sexually active groups. Subsequently, we allow persons with AIDS to be
+            sexually active, fixing their transmission rates (&#x03B2;<sub>AIDS</sub>) to be the
+            same across all CCR5 genotypes, and lower than transmission rates for primary-stage
+            infection (as the viral burden on average is not as high as during the acute phase), and
+            larger than transmission rates for asymptomatic-stage infection (as the viral burden
+            characteristically increases during the end stage of disease).</p>
+        </sec>
+        <sec>
+          <title>Disease progression.</title>
+          <p>We assume three stages of HIV infection: primary (acute, stage A), asymptomatic HIV
+            (stage B), and AIDS. The rates of transition through the first two stages are denoted by
+            &#x03B3;<sub>
+              <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+            </sub>
+<italic>i</italic>
+            ,<italic>j</italic>,<italic>k</italic>, where <italic>i</italic> represents genotype, <italic>
+            j</italic> is male/female, and <italic>k</italic> represents either stage A or stage B.
+            Transition rates through each of these stages are assumed to be inversely proportional
+            to the duration of that stage; however, other distributions are possible (<xref
+              ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B44">44</xref>, <xref
+              ref-type="bibr" rid="B45">45</xref>). Although viral loads generally peak in the first
+            2 months of infection, steady-state viral loads are established several months beyond
+            this (<xref ref-type="bibr" rid="B46">46</xref>). For group A, the primary
+            HIV-infecteds, duration is assumed to be 3.5 months. Based on results from European
+            cohort studies (<xref ref-type="bibr" rid="B7">7</xref>&#x2013;<xref ref-type="bibr"
+              rid="B10">10</xref>), the beneficial effects of the CCR5 W/&#x0394;32 genotype are
+            observed mainly in the asymptomatic years of HIV infection; &#x2248;7 years after
+            seroconversion survival rates appear to be quite similar between heterozygous and
+            homozygous individuals. We also assume that CCR5&#x0394;32/&#x0394;32-infected
+            individuals and wild-type individuals progress similarly, and that men and women
+            progress through each disease stage at the same rate. Given these observations, and that
+            survival after infection may be shorter in untreated populations, we choose the duration
+            time in stage B to be 6 years for wild-type individuals and 8 years for heterozygous
+            individuals. Transition through AIDS, &#x03B4;<sub>AIDS</sub>, is inversely proportional
+            to the duration of AIDS. We estimate this value to be 1 year for the time from onset of
+            AIDS to death. The progression rates are summarized in Table <xref ref-type="table"
+              rid="T3">3</xref>.</p>
+        </sec>
+      </sec>
+      <sec>
+        <title>Demographic Setting.</title>
+        <p>Demographic parameters are based on data from Malawi, Zimbabwe, and Botswana (<xref
+            ref-type="bibr" rid="B3">3</xref>, <xref ref-type="bibr" rid="B47">47</xref>). Estimated
+          birth and child mortality rates are used to calculate the annual numbers of children
+          (&#x03C7;<sub>
+            <italic>i</italic>,<italic>j</italic>
+          </sub>
+<italic>i</italic>,<italic>j</italic>)
+          maturing into the potentially sexually active, susceptible group at the age of 15 years (<xref
+            ref-type="bibr" rid="B3">3</xref>). For example, in the case where the mother is CCR5
+          wild type and the father is CCR5 wild type or heterozygous, the number of CCR5 W/W
+          children is calculated as follows &#x005B;<italic>s</italic>uppressing (<italic>t</italic>)
+          notation&#x005D;: &#x03C7;<sub>1,<italic>j</italic>
+          </sub>1,<italic>j</italic> = <disp-formula>
+            <tex-math id="M10">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$
+          B_{r}\hspace{.167em}{ \,\substack{ \\ {\sum} \\ _{k} }\, } \left[
+          S_{1,F}\frac{(S_{1,M}+I_{1,M,k})}{N_{M}}+ \left[
+          (0.5)S_{1,F}\frac{(S_{2,M}+I_{2,M,k})}{N_{M}} \right] + \right $$ \end{document} </tex-math>
+          </disp-formula>
+<disp-formula>
+            <tex-math id="M11">\documentclass[12pt]{minimal} \usepackage{wasysym}
+          \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb}
+          \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs}
+          \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {
+          &#x003C;-&#x003E; linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}
+          \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$ p_{v} \left \left(
+          \frac{(I_{1,F,k}(S_{1,M}+I_{1,M,k}))}{N_{M}}+ \left[
+          (0.5)I_{1,F,k}\frac{(S_{2,M}+I_{2,M,k})}{N_{M}} \right] \right) \right] ,\hspace{.167em}
+          $$ \end{document} </tex-math>
+          </disp-formula> where the probability of HIV
+          vertical transmission, 1 &#x2212; <italic>p<sub>v</sub>
+          </italic>, and the
+          birthrate, <italic>B<sub>r</sub>
+          </italic>, are both included in the equations
+          together with the Mendelian inheritance values as presented in Table <xref
+            ref-type="table" rid="T1">1</xref>. The generalized version of this equation (i.e.,
+          &#x03C7;<sub>
+            <italic>i</italic>,<italic>j</italic>
+          </sub>
+<italic>i</italic>,<italic>j</italic>)
+          can account for six categories of children (including gender and genotype). We assume that
+          all children of all genotypes are at risk, although we can relax this condition if data
+          become available to support vertical protection (e.g., ref. <xref ref-type="bibr"
+            rid="B48">48</xref>). All infected children are assumed to die before age 15. Before
+          entering the susceptible group at age 15, there is additional loss because of mortality
+          from all non-AIDS causes occurring less than 15 years of age at a rate of &#x03BC;<sub>
+          &#x03C7;</sub>&#x03C7; &#x00D7; &#x03C7;<sub>
+            <italic>i</italic>,<italic>j</italic>
+          </sub>
+<italic>i</italic>,<italic>j</italic>
+          (where &#x03BC;<sub>&#x03C7;</sub> is the mortality under 15 years of age). Children then
+          enter the population as susceptibles at an annual rate, &#x03C2;<sub>
+            <italic>j</italic>
+          </sub>
+<italic>j</italic> &#x00D7; &#x03C7;<sub>
+            <italic>i</italic>,<italic>j</italic>
+          </sub>
+<italic>i</italic>,<italic>j</italic>/15,
+          where &#x03C2;<sub>
+            <italic>j</italic>
+          </sub> distributes the children 51&#x0025; females and
+          49&#x0025; males. All parameters and their values are summarized in Table <xref
+            ref-type="table" rid="T4">4</xref>.</p>
+      </sec>
+    </sec>
+    <sec>
+      <title>Prevalence of HIV</title>
+      <sec>
+        <title>Demographics and Model Validation.</title>
+        <p>The model was validated by using parameters estimated from available demographic data.
+          Simulations were run in the absence of HIV infection to compare the model with known
+          population growth rates. Infection was subsequently introduced with an initial low HIV
+          prevalence of 0.5&#x0025; to capture early epidemic behavior.</p>
+        <p>In deciding on our initial values for parameters during infection, we use Joint United
+          Nations Programme on HIV&#x002F;AIDS national prevalence data for Malawi, Zimbabwe, and
+          Botswana. Nationwide seroprevalence of HIV in these countries varies from
+          &#x2248;11&#x0025; to over 20&#x0025; (<xref ref-type="bibr" rid="B3">3</xref>), although
+          there may be considerable variation within given subpopulations (<xref ref-type="bibr"
+            rid="B2">2</xref>, <xref ref-type="bibr" rid="B49">49</xref>).</p>
+        <p>In the absence of HIV infection, the annual percent population growth rate in the model
+          is &#x2248;2.5&#x0025;, predicting the present-day values for an average of sub-Saharan
+          African cities (data not shown). To validate the model with HIV infection, we compare our
+          simulation of the HIV epidemic to existing prevalence data for Kenya and Mozambique (<ext-link
+            ext-link-type="url" xmlns:xlink="http://www.w3.org/1999/xlink"
+            xlink:href="http://www.who.int/emc-hiv/fact-sheets/pdfs/kenya.pdf">
+          http://www.who.int/emc-hiv/fact-sheets/pdfs/kenya.pdf</ext-link> and ref. <xref
+            ref-type="bibr" rid="B51">51</xref>). Prevalence data collected from these countries
+          follow similar trajectories to those predicted by our model (Fig. <xref ref-type="fig"
+            rid="F2">2</xref>). </p>
+        <fig id="F2">
+          <label>Figure 2</label>
+          <caption>
+            <p>Model simulation of HIV infection in a population lacking the protective
+              CCR5&#x0394;32 allele compared with national data from Kenya (healthy adults) and
+              Mozambique (blood donors, ref. <xref ref-type="bibr" rid="B17">17</xref>). The
+              simulated population incorporates parameter estimates from sub-Saharan African
+              demographics. Note the two outlier points from the Mozambique data were likely caused
+              by underreporting in the early stages of the epidemic.</p>
+          </caption>
+          <graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="pq1813251002">
+          </graphic>
+        </fig>
+      </sec>
+      <sec>
+        <title>Effects of the Allele on Prevalence.</title>
+        <p>After validating the model in the wild type-only population, both CCR5&#x0394;32
+          heterozygous and homozygous people are included. Parameter values for HIV transmission,
+          duration of illness, and numbers of contacts per partner are assumed to be the same within
+          both settings. We then calculate HIV/AIDS prevalence among adults for total HIV/AIDS
+          cases.</p>
+        <p>Although CCR5&#x0394;32/&#x0394;32 homozygosity is rarely seen in HIV-positive
+          populations (prevalence ranges between 0 and 0.004&#x0025;), 1&#x2013;20&#x0025; of people
+          in HIV-negative populations of European descent are homozygous. Thus, to evaluate the
+          potential impact of CCR5&#x0394;32, we estimate there are 19&#x0025; CCR5 W/&#x0394;32
+          heterozygous and 1&#x0025; CCR5 &#x0394;32/&#x0394;32 homozygous people in our population.
+          These values are in Hardy-Weinberg equilibrium with an allelic frequency of the mutation
+          as 0.105573.</p>
+        <p>Fig. <xref ref-type="fig" rid="F3">3</xref> shows the prevalence of HIV in two
+          populations: one lacking the mutant CCR5 allele and another carrying that allele. In the
+          population lacking the protective mutation, prevalence increases logarithmically for the
+          first 35 years of the epidemic, reaching 18&#x0025; before leveling off. </p>
+        <fig id="F3">
+          <label>Figure 3</label>
+          <caption>
+            <p>Prevalence of HIV/AIDS in the adult population as predicted by the model. The top
+              curve (&#x25CB;) indicates prevalence in a population lacking the protective allele.
+              We compare that to a population with 19&#x0025; heterozygous and 1&#x0025; homozygous
+              for the allele (implying an allelic frequency of 0.105573. Confidence interval bands
+              (light gray) are shown around the median simulation (&#xE80B;) providing a range of
+              uncertainty in evaluating parameters for the effect of the mutation on the infectivity
+              and the duration of asymptomatic HIV for heterozygotes.</p>
+          </caption>
+          <graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="pq1813251003">
+          </graphic>
+        </fig>
+        <p>In contrast, when a proportion of the population carries the CCR5&#x0394;32 allele, the
+          epidemic increases more slowly, but still logarithmically, for the first 50 years, and
+          HIV/AIDS prevalence reaches &#x2248;12&#x0025; (Fig. <xref ref-type="fig" rid="F3">3</xref>).
+          Prevalence begins to decline slowly after 70 years.</p>
+        <p>In the above simulations we assume that people with AIDS are not sexually active.
+          However, when these individuals are included in the sexually active population the
+          severity of the epidemic increases considerably (data not shown). Consistent with our
+          initial simulations, prevalences are still relatively lower in the presence of the CCR5
+          mutation.</p>
+        <p>Because some parameters (e.g., rate constants) are difficult to estimate based on
+          available data, we implement an uncertainty analysis to assess the variability in the
+          model outcomes caused by any inaccuracies in estimates of the parameter values with regard
+          to the effect of the allelic mutation. For these analyses we use Latin hypercube sampling,
+          as described in refs. <xref ref-type="bibr" rid="B52">52</xref>&#x2013;<xref
+            ref-type="bibr" rid="B56">56</xref>, Our uncertainty and sensitivity analyses focus on
+          infectivity vs. duration of infectiousness. To this end, we assess the effects on the
+          dynamics of the epidemic for a range of values of the parameters governing transmission
+          and progression rates: &#x03B2;<sub>
+          &#x00EE;&#x0131;&#x0131;&#x005E;&#x005E;,&#xEB30;&#xE2D4;&#xE2D4;&#x005E;&#x005E;,&#xEA50;<italic>
+          k</italic>
+<italic>k</italic>&#x005E;&#x005E;&#x2192;<italic>i</italic>,<italic>j</italic>
+          </sub>
+          and &#x03B3;<sub>
+            <italic>i</italic>,<italic>j</italic>,<italic>k</italic>
+          </sub>
+<italic>i</italic>
+          ,<italic>j</italic>,<italic>k</italic>. All other parameters are held constant. These
+          results are presented as an interval band about the average simulation for the population
+          carrying the CCR5&#x0394;32 allele (Fig. <xref ref-type="fig" rid="F3">3</xref>). Although
+          there is variability in the model outcomes, the analysis indicates that the overall model
+          predictions are consistent for a wide range of transmission and progression rates.
+          Further, most of the variation observed in the outcome is because of the transmission
+          rates for both heterosexual males and females in the primary stage of infection (&#x03B2;<sub>
+          2,M,A</sub>
+<sub>&#x2192;</sub>
+<sub>
+            <italic>i</italic>
+          </sub>
+<sub>,F</sub>, &#x03B2;<sub>2,F,A</sub>
+<sub>&#x2192;</sub>
+<sub>
+            <italic>i</italic>
+          </sub>
+<sub>,M</sub>). As mentioned above, we assume lower
+          viral loads correlate with reduced infectivity; thus, the reduction in viral load in
+          heterozygotes has a major influence on disease spread.</p>
+      </sec>
+    </sec>
+    <sec>
+      <title>HIV Induces Selective Pressure on Genotype Frequency</title>
+      <p>To observe changes in the frequency of the CCR5&#x0394;32 allele in a setting with HIV
+        infection as compared with the Hardy-Weinberg equilibrium in the absence of HIV, we follow
+        changes in the total number of CCR5&#x0394;32 heterozygotes and homozygotes over 1,000 years
+        (Fig. <xref ref-type="fig" rid="F4">4</xref>). We initially perform simulations in the
+        absence of HIV infection as a negative control to show there is not significant selection of
+        the allele in the absence of infection. To determine how long it would take for the allelic
+        frequency to reach present-day levels (e.g., <italic>q</italic> = 0.105573), we initiate
+        this simulation for 1,000 years with a very small allelic frequency (<italic>q</italic> =
+        0.00105). In the absence of HIV, the allelic frequency is maintained in equilibrium as shown
+        by the constant proportions of CCR5&#x0394;32 heterozygotes and homozygotes (Fig. <xref
+          ref-type="fig" rid="F4">4</xref>, solid lines). The selection for CCR5&#x0394;32 in the
+        presence of HIV is seen in comparison (Fig. <xref ref-type="fig" rid="F4">4</xref>, dashed
+        lines). We expand the time frame of this simulation to 2,000 years to view the point at
+        which the frequency reaches present levels (where <italic>q</italic> &#x223C;0.105573 at
+        year = 1200). Note that the allelic frequency increases for &#x2248;1,600 years before
+        leveling off. </p>
+      <fig id="F4">
+        <label>Figure 4</label>
+        <caption>
+          <p>Effects of HIV-1 on selection of the CCR5&#x0394;32 allele. The Hardy-Weinberg
+            equilibrium level is represented in the no-infection simulation (solid lines) for each
+            population. Divergence from the original Hardy-Weinberg equilibrium is shown to occur in
+            the simulations that include HIV infection (dashed lines). Fraction of the total
+            subpopulations are presented: (<italic>A</italic>) wild types (W/W), (<italic>B</italic>)
+            heterozygotes (W/&#x0394;32), and (<italic>C</italic>) homozygotes
+            (&#x0394;32/&#x0394;32). Note that we initiate this simulation with a much lower allelic
+            frequency (0.00105) than used in the rest of the study to better exemplify the actual
+            selective effect over a 1,000-year time scale. (<italic>D</italic>) The allelic
+            selection effect over a 2,000-year time scale.</p>
+        </caption>
+        <graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="pq1813251004">
+        </graphic>
+      </fig>
+    </sec>
+    <sec sec-type="discussion">
+      <title>Discussion</title>
+      <p>This study illustrates how populations can differ in susceptibility to epidemic HIV/AIDS
+        depending on a ubiquitous attribute such as a prevailing genotype. We have examined
+        heterosexual HIV epidemics by using mathematical models to assess HIV transmission in
+        dynamic populations either with or without CCR5&#x0394;32 heterozygous and homozygous
+        persons. The most susceptible population lacks the protective mutation in CCR5. In less
+        susceptible populations, the majority of persons carrying the CCR5&#x0394;32 allele are
+        heterozygotes. We explore the hypothesis that lower viral loads (CCR5&#x0394;32
+        heterozygotes) or resistance to infection (CCR5&#x0394;32 homozygotes) observed in persons
+        with this coreceptor mutation ultimately can influence HIV epidemic trends. Two contrasting
+        influences of the protective CCR5 allele are conceivable: it may limit the epidemic by
+        decreasing the probability of infection because of lower viral loads in infected
+        heterozygotes, or it may exacerbate the epidemic by extending the time that infectious
+        individuals remain in the sexually active population. Our results strongly suggest the
+        former. Thus, the absence of this allele in Africa could explain the severity of HIV disease
+        as compared with populations where the allele is present.</p>
+      <p>We also observed that HIV can provide selective pressure for the CCR5&#x0394;32 allele
+        within a population, increasing the allelic frequency. Other influences may have
+        additionally selected for this allele. Infectious diseases such as plague and small pox have
+        been postulated to select for CCR5&#x0394;32 (<xref ref-type="bibr" rid="B57">57</xref>, <xref
+          ref-type="bibr" rid="B58">58</xref>). For plague, relatively high levels of CCR5&#x0394;32
+        are believed to have arisen within &#x2248;4,000 years, accounting for the prevalence of the
+        mutation only in populations of European descent. Smallpox virus uses the CC-coreceptor,
+        indicating that direct selection for mutations in CCR5 may have offered resistance to
+        smallpox. Given the differences in the epidemic rates of plague (<xref ref-type="bibr"
+          rid="B59">59</xref>), smallpox, and HIV, it is difficult to directly compare our results
+        to these findings. However, our model suggests that the CCR5&#x0394;32 mutation could have
+        reached its present allelic frequency in Northern Europe within this time frame if selected
+        for by a disease with virulence patterns similar to HIV. Our results further support the
+        idea that HIV has been only recently introduced as a pathogen into African populations, as
+        the frequency of the protective allele is almost zero, and our model predicts that selection
+        of the mutant allele in this population by HIV alone takes at least 1,000 years. This
+        prediction is distinct from the frequency of the CCR5&#x0394;32 allele in European
+        populations, where pathogens that may have influenced its frequency (e.g., <italic>Yersinia
+        pestis</italic>) have been present for much longer.</p>
+      <p>Two mathematical models have considered the role of parasite and host genetic heterogeneity
+        with regard to susceptibility to another pathogen, namely malaria (<xref ref-type="bibr"
+          rid="B60">60</xref>, <xref ref-type="bibr" rid="B61">61</xref>). In each it was determined
+        that heterogeneity of host resistance facilitates the maintenance of diversity in parasite
+        virulence. Given our underlying interest in the coevolution of pathogen and host, we focus
+        on changes in a host protective mutation, holding the virulence of the pathogen constant
+        over time.</p>
+      <p>Even within our focus on host protective mutations, numerous genetic factors, beneficial or
+        detrimental, could potentially influence epidemics. Other genetically determined host
+        factors affecting HIV susceptibility and disease progression include a CCR5 A/A to G/G
+        promoter polymorphism (<xref ref-type="bibr" rid="B62">62</xref>), a CCR2 point mutation (<xref
+          ref-type="bibr" rid="B11">11</xref>, <xref ref-type="bibr" rid="B63">63</xref>), and a
+        mutation in the CXCR4 ligand (<xref ref-type="bibr" rid="B64">64</xref>). The CCR2b
+        mutation, CCR264I, is found in linkage with at least one CCR5 promoter polymorphism (<xref
+          ref-type="bibr" rid="B65">65</xref>) and is prevalent in populations where CCR5&#x0394;32
+        is nonexistent, such as sub-Saharan Africa (<xref ref-type="bibr" rid="B63">63</xref>).
+        However, as none of these mutations have been consistently shown to be as protective as the
+        CCR5&#x0394;32 allele, we simplified our model to incorporate only the effect of
+        CCR5&#x0394;32. Subsequent models could be constructed from our model to account for the
+        complexity of multiple protective alleles. It is interesting to note that our model predicts
+        that even if CCR264I is present at high frequencies in Africa, its protective effects may
+        not augment the lack of a protective allele such as CCR5&#x0394;32.</p>
+      <p>Although our models demonstrate that genetic factors can contribute to the high prevalence
+        of HIV in sub-Saharan Africa, demographic factors are also clearly important in this region.
+        Our models explicitly incorporated such factors, for example, lack of treatment
+        availability. Additional factors were implicitly controlled for by varying only the presence
+        of the CCR5&#x0394;32 allele. More complex models eventually could include interactions with
+        infectious diseases that serve as cofactors in HIV transmission. The role of high sexually
+        transmitted disease prevalences in HIV infection has long been discussed, especially in
+        relation to core populations (<xref ref-type="bibr" rid="B15">15</xref>, <xref
+          ref-type="bibr" rid="B50">50</xref>, <xref ref-type="bibr" rid="B66">66</xref>). Malaria,
+        too, might influence HIV transmission, as it is associated with transient increases in semen
+        HIV viral loads and thus could increase the susceptibility of the population to epidemic HIV
+        (<xref ref-type="bibr" rid="B16">16</xref>).</p>
+      <p>In assessing the HIV/AIDS epidemic, considerable attention has been paid to the influence
+        of core groups in driving sexually transmitted disease epidemics. Our results also highlight
+        how characteristics more uniformly distributed in a population can affect susceptibility. We
+        observed that the genotypic profile of a population affects its susceptibility to epidemic
+        HIV/AIDS. Additional studies are needed to better characterize the influence of these
+        genetic determinants on HIV transmission, as they may be crucial in estimating the severity
+        of the epidemic in some populations. This information can influence the design of treatment
+        strategies as well as point to the urgency for education and prevention programs.</p>
+    </sec>
+  </body>
+  <back>
+    <ack>
+      <p>We thank Mark Krosky, Katia Koelle, and Kevin Chung for programming and technical
+        assistance. We also thank Drs. V. J. DiRita, P. Kazanjian, and S. M. Blower for helpful
+        comments and discussions. We thank the reviewers for extremely insightful comments.</p>
+    </ack>
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