Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity

Abstract

The extent to which viral genetic context influences HIV adaptation to human leukocyte antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D cocirculate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA gag, pol, and nef sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtype A1 or D. Using phylogenetically informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtype A1 and/or D had previously been reported in subtype B, C, and/or circulating recombinant form 01_AE (CRF01_AE), confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of the identified HLA-associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype-specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype-specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm that HIV genetic context is a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies. IMPORTANCE The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B and, to a lesser extent, subtype C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. The results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational cytotoxic T-lymphocyte-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines.

Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5

“…HIV group M subtypes A, B, C and D collectively account for ~75% of the global pandemic. Nef is a crucial determinant of viral pathogenesis, and also ranks among the most variable regions in the HIV genome [ 40 , 41 ], suggesting that differences in Nef function may contribute to clinical outcome. Our analysis of 339 diverse Nef clones from these four major HIV subtypes demonstrates that subtype A and C clones displayed lower ability to internalize SERINC5 compared to those from subtypes B and D. This raises the intriguing possibility that an attenuated capacity to counteract SERINC5 may contribute to decreased pathogenesis in the context of subtype A or C infection, which has been seen in regions where these strains co-circulate with subtype D [ 24 ].…”

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

“…pUL26 activity appears to be supported by two other tegument proteins pUL25 and pp65 [ 211 ]. HCMV also uses another tegument protein pUL50 to affect ISGylation by targeting UBE1L, an important ligase responsible for ISG15 linkage, for proteasomal degradation [ 212 ]. Since ISGylation also regulates the activation of IFN-related pathways, some viruses have harnessed ISGylation to favor their replication.…”

Effect of Difference in Consensus Sequence between HIV-1 Subtype A/E and Subtype B Viruses on Elicitation of Gag-Specific CD8+T Cells and Accumulation of HLA-Associated Escape Mutations

“…Since HLA class I allele distributions differ among racial and ethnic groups worldwide (15), the pattern and diversity of HLA-APs are somewhat distinct to each race and region (9,13). In addition, a difference in sequences among HIV-1 subtypes may affect the diversity of HLA-APs (16). Thus, information about HLA-APs among different HIV-1 subtypes will be useful for development of a universal HIV-1 vaccine.…”

“…Thus, the difference in consensus sequence affected the elicitation of HLA-C*01:02-restricted GagYI9-specific T cells but not that of HLA-B*52:01-restricted RI8-specific T cells. These findings account for the difference in the accumulation of HLA-associated Gag280 mutations between the subtype A/E and B infections.A previous study on HLA-APs in Uganda revealed that 34% of the identified HLA-associated polymorphisms were significantly and differentially selected between subtypes A1 and D(16). This study showed only that the subtype A1 consensus peptide had stronger affinity for HLA-B*15:03 than the subtype D consensus peptide, as found from the analysis of one case of these HLA-APs, Nef K105R, which is selected due to theon January 3, 2021 by guest http://jvi.asm.org/ Downloaded from 20 presence of putative HLA-B*15:03-restricted epitope NefRL9 in subtype A1 but not D. Thus, this study implied that the difference in consensus sequence affects the selection of CTL escape mutations.…”