6 research outputs found
HLA-Driven Convergence of HIV-1 Viral Subtypes B and F Toward the Adaptation to Immune Responses in Human Populations
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 & Wilkins