Molecular Evolution of HIV-1 CRF01_AE Env in Thai Patients

Abstract

BackgroundThe envelope glycoproteins (Env), gp120 and gp41, are the most variable proteins of human immunodeficiency virus type 1 (HIV-1), and are the major targets of humoral immune responses against HIV-1. A circulating recombinant form of HIV-1, CRF01_AE, is prevalent throughout Southeast Asia; however, only limited information regarding the immunological characteristics of CRF01_AE Env is currently available. In this study, we attempted to examine the evolutionary pattern of CRF01_AE Env under the selection pressure of host immune responses.Methodology/Principal FindingsPeripheral blood samples were collected periodically over 3 years from 15 HIV-1-infected individuals residing in northern Thailand, and amplified env genes from the samples were subjected to computational analysis. The V5 region of gp120 showed highest variability in several samples over 3 years, whereas the V1/V2 and/or V4 regions of gp120 also showed high variability in many samples. In addition, the N-terminal part of the C3 region of gp120 showed highest amino acid diversity among the conserved regions of gp120. Chronological changes in the numbers of amino acid residues in gp120 variable regions and potential N-linked glycosylation (PNLG) sites are involved in increasing the variability of Env gp120. Furthermore, the C3 region contained several amino acid residues potentially under positive selection, and APOBEC3 family protein-mediated G to A mutations were frequently detected in such residues.Conclusions/SignificanceSeveral factors, including amino acid substitutions particularly in gp120 C3 and V5 regions as well as changes in the number of PNLG sites and in the length of gp120 variable regions, were revealed to be involved in the molecular evolution of CRF01_AE Env. In addition, a similar tendency was observed between CRF01_AE and subtype C Env with regard to the amino acid variation of gp120 V3 and C3 regions. These results may provide important information for understanding the immunological characteristics of CRF01_AE Env.

HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug

“…Furthermore, CRF01_AE variation at H375 is minimal, even though the C3 region showed the highest rates of amino acid diversity among conserved regions of gp120 and appeared important in CRF01_AE HIV-1 quasispecies evolution (6). Coupled with the finding that all other subtypes and CRFs analyzed have greater entropy and an absolute nonoccurrence of H at gp120 position 375, our observations suggest that H375 may confer an evolutionary advantage/constraint in the context of CRF01_AE HIV-1 infection, distinct from the drug resistance observed in this study.…”

“…Since CD4-F43 insertion into the CD4-F43 cavity (Fig. 6H, I) accounts for 23% of the CD4-gp120 interaction face (6,32) and is critical for HIV-1 entry into host cells, this competition (Fig. 6F, G, K) could account for the strong subtype B HIV-1 inhibition demonstrated by this drug.…”

CRF01_AE-Specific Neutralizing Activity Observed in Plasma Derived from HIV-1-Infected Thai Patients Residing in Northern Thailand: Comparison of Neutralizing Breadth and Potency between Plasma Derived from Rapid and Slow Progressors

“…In addition, structural differences between subtype B and C Env molecules have recently been reported [31]. Moreover, our recent observations suggested that different Env regions were affected by host immune pressure between CRF01_AE and subtype B viruses [32]. Taken together with the results in this report, we believe that it is important to take into account the antigenic and immunogenic diversity among different subtypes and CRFs of HIV-1 in developing HIV-1 vaccine antigens to elicit a broadly neutralizing antibody response.…”

Impact of amino acid substitutions in the V2 and C2 regions of human immunodeficiency virus type 1 CRF01_AE envelope glycoprotein gp120 on viral neutralization susceptibility to broadly neutralizing antibodies specific for the CD4 binding site

“…Our previous report showed that high amino acid variability was observed in the V2 region, as well as in the V1, V4 and V5 regions, of Env gp120 among viral genomic fragments continuously collected for a short period (3 years) from CRF01_AE-infected Thai individuals [ 48 ], suggesting that the virus constantly evolved by introducing mutations in the V2 region of gp120, presumably in order to counteract anti-HIV-1 humoral immune responses. Env gp120 and gp41 are the major targets of anti-HIV-1 neutralizing antibodies, and are therefore candidates for vaccine antigens.…”