The characteristics of the HIV-1 Env glycoprotein contribute to viral pathogenesis

Abstract

The understanding of HIV-1 pathogenesis and clinical progression is incomplete because of the variable contribution of host, immune and viral factors. The involvement of viral factors has been investigated in extreme clinical phenotypes from rapid progressors to long-term non-progressors (LTNPs). Among HIV-1 proteins, the envelope glycoprotein complex (Env) has concentrated many studies for its important role in the immune response and in the first steps of viral replication. In this study, we analyzed the contribution of 41 Envs from 24 patients with different clinical progression rates and viral loads (VLs), LTNP-Elite Controllers (LTNP-ECs); Viremic LTNPs (vLTNPs), and non-controllers individuals contemporary to LTNPs or recent, named Old and Modern progressors. We analyzed the Env expression, the fusion and cell-to-cell transfer capacities as well as viral infectivity. The sequence and phylogenetic analysis of Envs were also performed. In every functional characteristic, the Envs from subjects with viral control (LTNP-ECs and vLTNPs) showed significant lower performance compared to those from the progressor individuals (Old and Modern). Regarding sequence analysis, the variable loops of the gp120 subunit of the Env (i.e., V2, V4 and mainly V5) of the progressor individuals showed longer and more glycosylated sequences than controller subjects. Therefore, HIV-1 Envs presenting poor viral functions and shorter sequences were associated with viremic control and the non-progressor clinical phenotype, whereas functional Envs were associated with the lack of virological control and progressor clinical phenotypes. These correlations support the central role of Env genotypic and phenotypic characteristics in the in vivo HIV-1 infection and pathogenesis. IMPORTANCEThe role of the virus in the pathogenesis of HIV-1 infection has not been investigated in isolates from individuals with different progression rates. In this work, we studied the properties of the envelope glycoprotein complex (Env) in individuals with different progression rates to elucidate its role in pathogenesis. We estimated the Env expression, the CD4 binding, the fusion and cell-to-cell viral transfer capacities that affect the infectivity of the viral Envs in recombinant viruses. The Envs from individuals which control viral replication and lack clinical progression (LTNP-ECs and vLTNPs) showed lower functional capacities than from subjects with clinical progression (Old and Modern). The functional increase of the Envs characteristics was associated with an increase in viral infectivity and in increased length of variable loops and the number of glycosylation sites of the Env (gp120/SU). These results support the concept that viral characteristics contribute to viral infection and pathogenesis.