Increasingly Successful Highly Active Antiretroviral Therapy Delays the Emergence of New HLA Class I-Associated Escape Mutations in HIV-1

BC Centre for Excellence in HIV/AIDS, Vancouver, Canada.
Clinical Infectious Diseases (Impact Factor: 8.89). 03/2012; 54(11):1652-9. DOI: 10.1093/cid/cis253
Source: PubMed
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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    • "In most cases, this combines the use of two nucleoside analogs and one protease inhibitor [82]. The combination strategy appears to overcome the ability of the virus to rapidly produce mutants that are drug resistant [83]. In many cases, HAART has lowered viral load to levels that are not detectable by current methods and has improved the health of AIDS patients to the point that they can again function at a normal level [84]. "
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    • "Similarly , in a more recent study of 20 patients with VL < 50 copies/mL, sequences were obtained for 12 study participants, and evidence for selection of CTL escape mutations was found in three patients (Shiu et al., 2009). These five studies all found evidence of accumulation of CTL escape mutations during ART, with the rate of accumulation correlated with the level of ongoing viral replication in two studies (Shiu et al., 2009; Knapp et al., 2012 ). This observation may indicate that at lower VLs, CTL responses exert less pressure on the virus, due to the reduced number of circulating HIV-specific CTL (see below). "
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