Increasingly Successful Highly Active Antiretroviral Therapy Delays the Emergence of New HLA Class I-Associated Escape Mutations in HIV-1
ABSTRACT HLA class I-restricted cytotoxic T lymphocytes and highly active antiretroviral therapy (HAART) exert strong selective pressures on human immunodeficiency virus type 1 (HIV-1), leading to escape mutations compromising virologic control. Immune responses continue to shape HIV-1 evolution after HAART initiation, but the extent and rate at which this occurs remain incompletely quantified. Here, we characterize the incidence and clinical correlates of HLA-associated evolution in HIV-1 Pol after HAART initiation in a large, population-based observational cohort.
British Columbia HAART Observational, Medical Evaluation and Research cohort participants with available HLA class I types and longitudinal posttherapy protease/reverse transcriptase sequences were studied (n = 619; median, 5 samples per patient and 5.2 years of follow-up). HLA-associated polymorphisms were defined according to published reference lists. Rates and correlates of immune-mediated HIV-1 evolution were investigated using multivariate Cox proportional hazard models incorporating baseline and time-dependent plasma viral load and CD4 response data.
New HLA-associated escape events were observed in 269 (43%) patients during HAART and occurred at 49 of 63 (78%) investigated immune-associated sites in Pol. In time-dependent analyses adjusting for baseline factors, poorer virologic, but not immunologic, response to HAART was associated with increased risk of immune escape of 1.9-fold per log(10) viral load increment (P < .0001). Reversion of escape mutations following HAART initiation was extremely rare.
HLA-associated HIV-1 evolution continues during HAART to an extent that is inversely related to the virologic success of therapy. Minimizing the degree of immune escape could represent a secondary benefit of effective HAART.
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ABSTRACT: Background HIV patients on suppressive antiretroviral therapy have undetectable viremia making it impossible to screen plasma HIV tropism if regimen change is required during suppression. We investigated the prevalence and predictors of tropism switch from CCR5-using (“R5”) to non-CCR5-using (“non-R5”) before and after viral suppression in the initially therapy-naïve HOMER cohort from British Columbia, Canada. Methods We compared pre-therapy and post-suppression viral genotypic tropism in patients who initiated on PI/NNRTI-based antiretroviral regimens between 1996-1999 (n = 462). Virologic suppression was defined as having two consecutive viral loads of <500 copies/mL, which was the sensitivity limit of most viral load assays at the time. Viral tropism was inferred by V3-loop-population-sequencing and geno2pheno[coreceptor] with cutoff at 5.75% false positive rate (FPR). Results When virologic suppression was defined as two-consecutive viral loads <500 copies/mL, 34 (9%) of the 397 patients with pre-therapy R5-virus switched to non-R5 at viral load rebound after a median of 19 months (IQR 8–41 months) of undetectable viremia. Duration of viral load suppression was not a predictor of switch, but lower CD4 count during suppression (median 400 versus 250 cells/mL) and an increased prevalence of pre-therapy non-R5 HIV by “deep” sequencing (median 0.2% versus 3.2%) were independently associated with switch (p = 0.03 and p<0.0001, respectively). Conclusion R5-to-non-R5 tropism switches in plasma virus after undetectable viremia were relatively rare events especially among patients with higher CD4 counts during virologic suppression. Our study supports the use of pre-suppression tropism results if maraviroc is being considered during virologic suppression in this subgroup of patients.PLoS ONE 06/2014; 9(6):e99000. DOI:10.1371/journal.pone.0099000 · 3.53 Impact Factor
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ABSTRACT: Pharmacological reactivation of human immunodeficiency virus (HIV) expression from latent proviruses coupled with fully suppressive antiretroviral therapy (ART) has been suggested as a strategy to eradicate HIV infection. In order for this strategy to be effective, latently infected cells must be killed either by the cytopathic effect of reactivated HIV gene expression, or by HIV-specific cytotoxic T lymphocyte (CTL). However, a review of current data reveals little evidence that CTL retain an antiviral effector capacity in patients on fully suppressive ART, implying that the HIV-specific CTL present in these patients will not be able to eliminate HIV-infected CD4 T cells effectively. If this is due to functional impairment or a quantitative deficit of HIV-specific CTL during ART, then therapeutic vaccination may improve the prospects for eradicating latent reservoirs. However, data from the macaque simian immunodeficiency virus (SIV) model indicate that , SIV-specific CTL are only effective during the early stages of the viral replication cycle, and this constitutes an alternative explanation why HIV-specific CTL do not appear to have an impact on HIV reservoirs during ART. In that case, immunotoxins that target HIV-expressing cells may be a more promising approach for HIV eradication.Frontiers in Immunology 03/2013; 4:52. DOI:10.3389/fimmu.2013.00052
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ABSTRACT: To determine whether residual plasma viremia in HIV(+) patients on nevirapine-including antiretroviral therapy (ART) is related to anti-HIV cellular immune responses, a case-control study was conducted comparing residual viremia in patients with detectable and undetectable Gag-specific T-cell responses. Gag-specific responses were measured by IFN-γ ELISpot. Residual viremia was determined at two consecutive hospital visits by an ultra-sensitive technique with a detection limit of 2 copies/ml. Median residual viremia was not different in patients with a positive Gag-specific ELISpot (n = 25) compared to those with a negative Gag-specific ELISpot (n = 30, P = 0.91). Ten of 25 (40%) patients with consistent detectable residual viremia and 4 of 12 (33%) patients with consistently undetectable residual viremia had a positive Gag-specific ELISpot. Undetectable residual viremia was associated with the duration of ART including nevirapine (P < 0.05), but not with the Gag-specific ELISpot response. Gag-specific CTL in patients on ART therefore appear to have no impact on the virus-producing cells that are responsible for residual viremia during ART. J. Med. Virol. 9999:1-6, 2013. © 2013 Wiley Periodicals, Inc.Journal of Medical Virology 06/2014; 86(6). DOI:10.1002/jmv.23743 · 2.22 Impact Factor