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.

The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM͞TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus inf luence susceptibility to HAM͞TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM͞TSP (P < 0.0001), preventing 28% of potential cases of HAM͞TSP. Furthermore, HLA-A*02 ؉ healthy HTLV-I carriers have a proviral load one-third that (P ‫؍‬ 0.014) of HLA-A*02 ؊ HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM͞TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

Many physicians delay HAART in patients presenting with TB because of pill burden, drug/drug interactions and toxicity. Although the use of HAART led to significant reductions in viral load, ADI and mortality, co-infected patients commonly experienced AE leading to interruptions in TB/HIV therapy. We therefore recommend starting HAART early for patients with advanced HIV disease (CD4 < 100 x 106 cells/l) and deferring HAART until the continuation phase of TB therapy (i.e. after 2 months) for patients who are clinically stable (CD4 > 100 x 106 cells/l).

MTCT rates in the UK and Ireland have continued to decline since 2006, reaching an all-time low of 5 per 1000 in 2010-2011. This was primarily because of a reduction in transmissions associated with late initiation or nonreceipt of antenatal cART, and an increase in the proportion of women on cART at conception.