Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

Abstract

AbstractBackgroundHIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression.MethodsTwelve treatment-naïve, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures.ResultsIn total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28–37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7×10−3 versus 1.4×10−3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors – synonymous rates: 4.6×10−3 vs. 2.3×10−3; and nonsynonymous rates: 6.9×10−4 vs. 2.7×10−4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface.ConclusionsFaster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target.