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

Risk of cancers during interrupted antiretroviral therapy in the SMART study

Objective: To compare rates of AIDS-defining and non-AIDS-defining malignancies between patients on a CD4 T-cell-guided antiretroviral therapy (ART) strategy and continuous ART. Design: A randomized clinical trial. Methods: Malignancy rates were compared between the drug conservation arm in which ART was stopped if the CD4 T-cell count exceeded 350 cells/mu l and (re)started if it fell to less than 250 cells/mu l and the viral suppression arm utilizing continuous ART. Cox models were used to examine baseline characteristics including age, sex, race, cigarette use, previous malignancies, CD4 T-cell and HIV-RNA levels, hepatitis B or C, and ART duration. Results: A total of 5472 participants were randomly assigned to treatment groups, of whom 70 developed cancer: 13 AIDS-defining malignancies and 58 non-AIDS-defining malignancies (one patient had both). The AIDS-defining malignancy rate per 1000 person-years was higher in the drug conservation arm (3.0 versus 0.5). Proximal CD4 T-cell and HIV RNA levels mediated much of this increased risk. The drug conservation arm also had higher rates of Kaposi’s sarcoma (1.9 versus 0.3) and lymphoma (Hodgkin’s and non-Hodgkin’s; 1.1 versus 0.3). The non-AIDS-defining malignancy rate was similar between the drug conservation and viral suppression arms (8.8 versus 7.1). The most common non-AIDS-defining malignancies were skin (n = 16), lung (n = 8) and prostate (n = 6) cancers. Conclusion: Non-AIDS-defining malignancies were more common in this cohort than AIDS-defining malignancies. This analysis provides further evidence against the use of CD4 T-cell-guided ART because of a higher risk of AIDS-defining malignancies in addition to opportunistic infections and deaths. (C) 2007 Lippincott Williams &amp; Wilkins