Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes

Abstract

Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity.

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

“…This is consistent with previous reports that randomly introduced mutations were mostly deleterious to protease enzymatic activity or HIV-1 replication capacity [34, 64–66]. Random mutagenesis in other viruses also revealed a lack of beneficial mutations in well-adapted systems [65, 67–69]. DRAMs in particular were also reported to be deleterious to virus replication [31, 44].…”

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

“…This is consistent with previous reports that randomly introduced mutations were mostly deleterious to protease enzymatic activity or HIV-1 replication capacity [ 34 , 72 – 74 ]. Random mutagenesis in other viruses also revealed a lack of beneficial mutations in well-adapted systems [ 73 , 75 – 77 ]. RAMs in particular were also reported to be deleterious to virus replication [ 31 , 44 ].…”

Comprehensive analysis of HIV elite controllers’ and progressors’ transcriptional profiles from CD8+T lymphocytes demonstrates heterogeneity of pathways and master regulators, which may be essential for disease nonprogression

“…Thus, CD8 + lymphocytes can also exhibit noncytotoxic anti-HIV functions through the secretion of chemokines that compete with HIV particles for the corresponding coreceptors (19). CD8 + lymphocytes from ECs have T-cell receptors capable of broader cross-recognition of mutated epitopes from HIV gag antigens, which may be a consequence of the presence of HLA-I polymorphisms, e.g., HLA-B*57 and B*27, that influence the selection of T cell clones in the thymus (18, 19, 22, 32). CD8 + lymphocytes from ECs do not demonstrate an “exhaustion” state and have preserved functions related to cytotoxic and noncytotoxic responses (18, 19, 22, 24), including the ability to degranulate and secrete cytokines with anti-HIV effects, such as MIP-1α/β, RANTES, IFN-γ, TNF-α, and IL-2.…”