HLA-Driven Convergence of HIV-1 Viral Subtypes B and F Toward the Adaptation to Immune Responses in Human Populations

BACKGROUND: Cytotoxic T-Lymphocyte (CTL) response drives the evolution of HIV-1 at a host-level by selecting HLA-restricted escape mutations. Dissecting the dynamics of these escape mutations at a population-level would help to understand how HLA-mediated selection drives the evolution of HIV-1. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a study of the dynamics of HIV-1 CTL-escape mutations by analyzing through statistical approaches and phylogenetic methods the viral gene gag sequenced in plasma samples collected between the years 1987 and 2006 from 302 drug-naive HIV-positive patients. By applying logistic regression models and after performing correction for multiple test, we identified 22 potential CTL-escape mutations (p-value<0.05; q-value<0.2); 10 of these associations were confirmed in samples biologically independent by a Bayesian Markov Chain Monte-Carlo method. Analyzing their prevalence back in time we found that escape mutations that are the consensus residue in samples collected after 2003 have actually significantly increased in time in one of either B or F subtype until becoming the most frequent residue, while dominating the other viral subtype. Their estimated prevalence in the viral subtype they did not dominate was lower than 30% for the majority of samples collected at the end of the 80's. In addition, when screening the entire viral region, we found that the 75% of positions significantly changing in time (p<0.05) were located within known CTL epitopes. CONCLUSIONS: Across HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic in our setting was related to an association with an HLA allele. The fact that these mutations accumulated in one of either B or F subtypes have also dominated the other subtype shows how this selection might be causing a convergence of viral subtypes to variants which are more likely to evade the immune response of the population where they circulate

Mother-to-Child transmission of HCV among HIV/HCV Co-infected women

BACKGROUND: Maternal human immunodeficiency virus (HIV) coinfection has been associated with increased hepatitis C virus (HCV) mother-to-child transmission (MTCT). We hypothesized that HCV/HIV-coinfected women with well-controlled HIV disease would not have increased HCV MTCT. METHODS: The NISDI Perinatal and LILAC cohorts enrolled HIV-infected pregnant women and their infants in Latin America and the Caribbean. This substudy evaluated the HCV infection status of mothers at participating sites and their live born, singleton infants who had a 6-month postnatal visit by December 31, 2008. Mothers who were anti-HCV-positive, or who had CD4 counts (cells/mm(3)) <200 with detectable HCV RNA, were considered HCV-infected. All HCV-infected women were tested for HCV RNA. Infants with HCV RNA were considered HCV-infected. RESULTS: Of 1042 enrolled women, 739 (71%) mother-infant pairs met the inclusion criteria. Of the 739 women, 67 (9%) were anti-HCV-positive and 672 anti-HCV-negative [68 (10%) with CD4 counts <200; of these, 3 (4.4%) were HCV RNA-positive]. Therefore, our study population comprised 70 HCV-infected (47 with HCV RNA) and 669 HCV-uninfected women (and their infants). Factors associated with maternal HCV infection included unemployment (odds ratio [OR] = 2.58); tobacco (OR = 1.73) or marijuana (OR = 3.88) use during pregnancy; enrollment HIV viral load ([VL] copies/mL) ≥10 000 (OR = 2.27); HIV clinical disease stage C (OR = 2.12); and abnormal alanine aminotransferase (OR = 4.24) or aspartate aminotransferase (OR = 11.98). Four of 47 infants (8.5%) born to HCV-viremic women were HCV-infected, and all 4 mothers had HIV VL <1000 at hospital discharge after delivery. CONCLUSIONS: HCV MTCT among HIV/HCV-coinfected women with well-controlled HIV disease may be lower than reported in other coinfected populations. Studies with longer infant follow-up are needed.Fil: Checa Cabot, Claudia A.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Stoszek, Sonia K.. Westat; Estados UnidosFil: Quarleri, Jorge Fabian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Losso, Marcelo H.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Ivalo, Silvina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Peixoto, Mario F.. Hospital Femina. Vertical Transmission Prevention Unit; BrasilFil: Pilotto, José H.. Hospital Geral de Nova Iguaçu and Laboratorio de AIDS e Imunologia Molecular; BrasilFil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Sidi, Leon C.. Hospital Federal dos Servidores do Estado; BrasilFil: Read, Jennifer. National Institutes of Health; Estados Unido

Antiretroviral Resistance among HIV Type 1-Infected Women First Exposed to Antiretrovirals during Pregnancy: Plasma versus PBMCs

Resistance-associated mutations (RAMs) in plasma samples from HIV-1-infected women who received antiretroviral (ARV) prophylaxis during pregnancy was assessed and correlated with the detection of RAMs in peripheral blood mononuclear cells (PMBCs). The study population was composed of HIV-1-infected women enrolled in a prospective cohort study in Latin America and the Caribbean (NISDI Perinatal Study) as of March 1, 2005, who were diagnosed with HIV-1 infection during the current pregnancy, who received ARVs during pregnancy for prevention of mother-to-child transmission of HIV-1, and who were followed through at least the 6–12 week postpartum visit. Plasma samples collected at enrollment during pregnancy and at 6–12 weeks postpartum were assayed for RAMs. Plasma results were compared to previously described PBMC results from the same study population. Of 819 enrolled subjects, 197 met the eligibility criteria. Nucleic acid amplification was accomplished in 123 plasma samples at enrollment or 6–12 weeks postpartum, and RAMs were detected in 22 (17.9%; 95%CI: 11.7–25.9%). Previous analyses had demonstrated detection of RAMs in PBMCs in 19 (16.1%). There was high concordance between RAMs detected in plasma and PBMC samples, with only eight discordant pairs. The prevalence of RAMs among these pregnant, HIV-1-infected women is high (>15%). Rates of detection of RAMs in plasma and PBMC samples were similar