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Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1<jats:sup>+<\/jats:sup>) and HIV-2<jats:sup>+<\/jats:sup>individuals, matched for CD4 T cell depletion, exhibited similar<jats:italic>gag<\/jats:italic>mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2<jats:sup>+<\/jats:sup>patients, despite the reduced viremia (undetectable to 2.6 \u00d7 10<jats:sup>4<\/jats:sup>RNA copies\/ml). However,<jats:italic>tat<\/jats:italic>mRNA transcripts were observed at significantly lower levels in HIV-2<jats:sup>+<\/jats:sup>patients, suggesting that the rate of<jats:italic>de novo<\/jats:italic>infection is decreased in these patients. Our data also reveal a direct relationship of<jats:italic>gag<\/jats:italic>and<jats:italic>tat<\/jats:italic>transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2<jats:sup>+<\/jats:sup>patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2<jats:sup>+<\/jats:sup>patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection.<\/jats:p>","DOI":"10.1128\/jvi.01921-10","type":"journal-article","created":{"date-parts":[[2010,12,16]],"date-time":"2010-12-16T04:04:41Z","timestamp":1292472281000},"page":"2429-2438","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients"],"prefix":"10.1128","volume":"85","author":[{"given":"Rui S.","family":"Soares","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. 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Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Manuela","family":"Doroana","sequence":"additional","affiliation":[{"name":"Cli\u0301nica Universita\u0301ria de Doenc\u0327as Infecciosas e Parasita\u0301rias, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Margarida","family":"Lucas","sequence":"additional","affiliation":[{"name":"Cli\u0301nica Universita\u0301ria de Medicina 2, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Francisco","family":"Antunes","sequence":"additional","affiliation":[{"name":"Cli\u0301nica Universita\u0301ria de Doenc\u0327as Infecciosas e Parasita\u0301rias, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Rui M. 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