Abstract
BackgroundCCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively.ResultsCompared to PA-R5 Envs, A-R5 Envs had enhanced fusogenicity in quantitative cell-cell fusion assays, and reduced sensitivity to inhibition by the fusion inhibitor T-20. Sequence analysis identified the presence of Asn 362 (N362), a potential N-linked glycosylation site immediately N-terminal to CD4-binding site (CD4bs) residues in the C3 region of gp120, more frequently in A-R5 Envs than PA-R5 Envs. N362 was associated with enhanced fusogenicity, faster entry kinetics, and increased sensitivity of Env-pseudotyped reporter viruses to neutralization by the CD4bs-directed Env mAb IgG1b12. Mutagenesis studies showed N362 contributes to enhanced fusogenicity of most A-R5 Envs. Molecular models indicate N362 is located adjacent to the CD4 binding loop of gp120, and suggest N362 may enhance fusogenicity by promoting greater exposure of the CD4bs and/or stabilizing the CD4-bound Env structure.ConclusionEnhanced fusogenicity is a phenotype of the A-R5 Envs studied, which was associated with the presence of N362, enhanced HIV-1 entry kinetics and increased CD4bs exposure in gp120. N362 contributes to fusogenicity of R5 Envs in a strain dependent manner. Our studies suggest enhanced fusogenicity of A-R5 Envs may contribute to CD4+ T-cell loss in subjects who progress to AIDS whilst harbouring R5 HIV-1 variants. N362 may contribute to this effect in some individuals.
Highlights
CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to acquired immunodeficiency syndrome (AIDS), but mechanisms underlying the pathogenicity of R5 strains are poorly understood
X4 or R5X4 variants are absent in 50–60% of HIV-1 infected individuals who progress to AIDS [10,11,12,13,14]
Enhanced fusogenicity of AIDS R5 (A-R5) envelope glycoprotein (Env) may contribute, at least in part, to CD4+ T-cell loss in subjects who progress to AIDS whilst harbouring R5 HIV-1 variants
Summary
CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. The gp120 and gp envelope glycoprotein (Env) complexes of human immunodeficiency virus type 1 (HIV-1) mediate viral entry into cells (reviewed in [1,2,3]). Coreceptor binding induces further conformational changes in gp that lead to fusion between the viral and cellular membranes and entry of the HIV-1 core into cells. Progression of HIV-1 infection from early, asymptomatic stages of disease to acquired immunodeficiency syndrome (AIDS) is associated with a switch in viral coreceptor specificity from CCR5-using (R5) viral strains to those able to use CXCR4 (X4) or both coreceptors (R5X4) in 40–50% of infected adults [4,5,6,7,8] (reviewed in [9]). The persistence of an exclusive R5 viral population in vivo is sufficient to cause immunodeficiency in the majority of HIV-1 infected individuals who progress to AIDS
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