HIV and SIV CTL escape: implications for vaccine design.

Treatment of infected patients with ABT-538, an inhibitor of the protease of human immunodeficiency virus type 1 (HIV-1), causes plasma HIV-1 levels to decrease exponentially (mean half-life, 2.1 +/- 0.4 days) and CD4 lymphocyte counts to rise substantially. Minimum estimates of HIV-1 production and clearance and of CD4 lymphocyte turnover indicate that replication of HIV-1 in vivo is continuous and highly productive, driving the rapid turnover of CD4 lymphocytes.

The probability of HIV-1 transmission per coital act in representative African populations is unknown. We aimed to calculate this probability overall, and to estimate how it is affected by various factors thought to influence infectivity. 174 monogamous couples, in which one partner was HIV-1 positive, were retrospectively identified from a population cohort in Rakai, Uganda. Frequency of intercourse and reliability of reporting within couples was assessed prospectively. HIV-1 seroconversion was determined in the uninfected partners, and HIV-1 viral load was measured in the infected partners. Adjusted rate ratios of transmission per coital act were estimated by Poisson regression. Probabilities of transmission per act were estimated by log-log binomial regression for quartiles of age and HIV-1 viral load, and for symptoms or diagnoses of sexually transmitted diseases (STDs) in the HIV-1-infected partners. The mean frequency of intercourse was 8.9 per month, which declined with age and HIV-1 viral load. Members of couples reported similar frequencies of intercourse. The overall unadjusted probability of HIV-1 transmission per coital act was 0.0011 (95% CI 0.0008-0.0015). Transmission probabilities increased from 0.0001 per act at viral loads of less than 1700 copies/mL to 0.0023 per act at 38 500 copies/mL or more (p=0.002), and were 0.0041 with genital ulceration versus 0.0011 without (p=0.02). Transmission probabilities per act did not differ significantly by HIV-1 subtypes A and D, sex, STDs, or symptoms of discharge or dysuria in the HIV-1-positive partner. Higher viral load and genital ulceration are the main determinants of HIV-1 transmission per coital act in this Ugandan population.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.