Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients

Abstract

In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I) -associated amino acid polymorphisms, presumed to refl ect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a signifi cant correlation between the number of Gag escape mutations targeted by specifi c HLA-B allele -restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specifi c CTL responses capable of driving virus escape in the donor may be of clinical benefi t to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fi tness costs could have a signifi cant impact on HIV-1 pathogenesis.

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 + T cells, and disease progression

“…Previously, our work, and that of others, showed that transmitted viral characteristics significantly correlate with early SPVL (11,13,14) as well as CD4 + T-cell decline up to 3 y postinfection (15). Here, we sought to determine the underlying mechanisms by which vRC of transmitted HIV-1 impacts the trajectory of CD4 decline even in the context of viral control by previously identified host factors, such as protective HLA alleles, that also impact disease progression.…”

“…The observation that not all individuals harboring such protective HLA class I alleles go on to become long-term nonprogressors suggests that other factors outside of host immunogenetics play a role in defining disease progression (12). Transmitted viral characteristics have been shown to impact viral load within heterosexual transmission pairs, suggesting that viral characteristics are heritable and can impact disease severity (11,13,14). Moreover, we recently showed that attenuated viral replicative capacity (vRC) of the transmitted virus, defined in vitro by the Gag sequence, was associated with a significant delay in CD4 + T-cell decline in individuals recently infected with HIV-1 subtype C (15).…”

Immune escape from HIV-specific antibody-dependent cellular cytotoxicity (ADCC) pressure

“…ADCC-forced mutations theoretically could incur some fitness cost to viral replicative capacity, similar to that observed for CTL escape variants (19). Constructing replicating viruses with ADCC-induced mutations will allow testing of this hypothesis.…”

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).…”