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.
Highlights
Human immunodeficiency virus type-1 (HIV-1) is characterized by extensive genetic heterogeneity [1], and is divided into four groups, M, O, N and P
The molecular evolution of CRF01_AE envelope glycoproteins (Env), which was presumably driven by the selection pressure of humoral immune responses, was studied in this report
The molecular evolution of CRF01_AE Env was studied using viral gene fragments periodically collected from 15 chronically human immunodeficiency virus type 1 (HIV-1)-infected Thai patients over 3 years. It was previously reported for subtype B Env that the V1/V2 regions of gp120 are under positive selection in vivo [43], and the expansion of V1/V2 regions along with the accumulation of potential N-linked glycosylation (PNLG) sites reduces the susceptibility of viruses to autologous neutralizing antibody [28]
Summary
Human immunodeficiency virus type-1 (HIV-1) is characterized by extensive genetic heterogeneity [1], and is divided into four groups, M (major), O (outlying), N (new or non-M, non-O) and P (pending). Recently established, broadly neutralizing human monoclonal antibodies derived from HIV-1 subtype A-infected individuals recognize conserved regions of the V2 and V3 regions [22], while several broadly neutralizing, human or murine monoclonal antibodies elicited by the HIV-1 subtype B antigen recognize CD4BS or V3 region of Env gp120 [18,23,24,25,26,27]. These results imply that the Env of different subtypes and CRFs show different antigenicity. In order to study the evolutionary pattern of CRF01_AE Env under host immune pressure, we examined the changes of HIV-1 Env amino acid sequences derived from chronically CRF01_AE-infected Thai patients over 3 years
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