HLA Class I-Driven Evolution of Human Immunodeficiency Virus Type 1 Subtype C Proteome: Immune Escape and Viral Load

Abstract

Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL)recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads ( ) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.Human immunodeficiency virus type 1 (HIV-1) infection can elicit strong human leukocyte antigen (HLA) class I-mediated immune responses from HIV-specific cytotoxic T lymphocytes (CTL) (55, 66), which are thought to be important mediators of disease progression. However, viral sequence changes in critical amino acid residues of HLA-presented epitopes and immediately surrounding regions can be selected for their ability to effectively reduce the potency of the CTL response during the course of infection (escape variants) (5,6,10,30,37,54,57). The selective pressure of this CTL escape can be balanced by viral fitness constraints (16,20,27,42,45,46,53), with several studies finding CTL escape variants that were less fit than the original strains (7,11,16,27,40,45,46,62). Importantly, studies of humans and of macaques have shown that some escape variants revert to the original sequence when infecting a host with a different HLA genotype (16,27,40), again suggesting that CTL escape in these instances was associated with a loss in viral fitness. Additional evidence demonstrates that despite reduced fitness, CTL escape variants can be transmitted from one host to another (2,28,29,40,41,47), suggesting that they can persist in a population with common HLA alleles. Indeed, viral loads have been found to be correlated with HLA supertype frequencies, suggesting a population-wide selection for CTL escape mediated by the more common HLA alleles (65).The identification of viral variants predicted to have higher viral fitness has important implications for vaccine design. A vaccine that elicits immune responses to the fittest viral variant(s) and blocks common immune escape routes may not necessarily pr...

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

“…Consistent with previous studies of HLA-APs in HIV clade B (2,16,18), HLA-APs were more frequently detected in Nef than in Gag and Pol. Also consistent with previous observations in Caucasian, African, Chinese, and Mexican populations (1,6,11,15,18), the number of HLA-B-associated polymorphisms in our cohort was higher than that of HLA-A-or HLA-C-associated polymorphisms, further supporting a dominant role of HLA-B in HIV evolution (32). An interesting feature of the Japanese population is that approximately 70% of individuals carry HLA-A*24:02 (23).…”

“…HLA-APs were more frequently detected in Nef (occurring at 45 of 206 codons [21.8%]) compared to Gag (51 of 500 codons [10.2%]) or Pol (51 of 947 codons [5.1%]). Although HLA class I allele frequencies in Japan are somewhat distinct globally, the distribution of HLA-APs across HIV-1 proteins was consistent with that reported in previous studies of other populations infected with clade B or C (1,2,6,7,16). Broken down by HLA locus, the numbers of HLA-A-, HLA-B-, and HLA-C-associated polymorphisms were 78, 140, and 66, respectively, numbers that were also consistent with previous reports from Caucasian and African cohorts that HLA-B alleles restrict more associations than HLA-A or HLA-C alleles (1,6,18).…”

“…H IV cytotoxic T lymphocyte (CTL) escape occurs in a manner that is highly reproducible in the context of the HLA class I alleles expressed by the host (1)(2)(3)(4)(5)(6)(7)(8). By extension, HIV sequences circulating in a given host population exhibit polymorphisms that reflect the HLA allele distribution of that population (9).…”

“…Because HLA class I allele distributions differ among racial and ethnic groups worldwide (10), the pattern and diversity of HLA-associated escape mutations are also likely to be somewhat distinct to each race and region. Numerous population-based studies identifying HLA-associated polymorphisms (HLA-APs) have been conducted in European, North American, Australian, and African cohorts (2,6,8). However, fewer have been undertaken in Asian cohorts, where HIV-1 prevalence is also substantial (11).…”

Transmitted/Founder HIV-1 Subtype C Viruses Show Distinctive Signature Patterns in Vif, Vpr, and Vpu That Are Under Subsequent Immune Pressure During Early Infection

“…11 Human leukocyte antigen (HLA) class I-mediated CTL responses are important predictors of disease progression 12 that drive virus escape mutations that are highly adapted to the host environment. 4,[13][14][15][16][17][18] Recent studies employing ultradeep sequencing 3,19 confirmed dramatic shifts in the frequencies of epitope variants during the first weeks of HIV infection.…”