Transmission of HIV-1 CTL Escape Variants Provides HLA-Mismatched Recipients with a Survival Advantage

Abstract

One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts.

Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

“…Consistently, in our study, examination of T/F virus sequence outside reactive T cell epitopes found that subjects with lower acute VL set points contained footprints of previous virus escape in B57/5801, B81, and B51 epitopes (Supplemental Table 1 and refs. 67,68). These escape variants have been associated with lower in vitro replication, suggesting the transmitted viruses of these subjects had poorer replicative fitness, which contributed to the lower set point VL observed in some subjects (37,(64)(65)(66)(67)(68).…”

“…67,68). These escape variants have been associated with lower in vitro replication, suggesting the transmitted viruses of these subjects had poorer replicative fitness, which contributed to the lower set point VL observed in some subjects (37,(64)(65)(66)(67)(68). Studies are ongoing in an extended patient set to examine associations of T cell responses with VL over the first 6 months of HIV-1 infection.…”

Host-Specific Adaptation of HIV-1 Subtype B in the Japanese Population

“…Protective HLA alleles, such as HLA-B*57, -B*58, and -B*27, select Gag mutations affecting viral replication in Caucasians and Africans (36)(37)(38)(39)(40)(41) that may also provide some clinical benefit if they are transmitted to hosts lacking these alleles (42,43). HLA-B*57, -B*58, and -B*27 are not present at appreciable frequencies in Japan (23).…”

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

“…This was shown in HLA-B57 patients infected with a virus carrying mutations specific for HLA-B57, which are known to markedly decrease viral fitness, and in patients infected with virus carrying crippling drug resistance mutations (46). During early infection, the viruses in these HLA-B57 patients had a reduced replication capacity that was associated with viral control in the first few years postinfection (46,47). In this study, we investigate infections with attenuated viruses by letting the founder virus start with a low fitness due to a preexisting escape mutation accompanied by an imperfect compensatory mutation (see Materials and Methods).…”