Genetic analysis of HIV-1 Circulating Recombinant Form 02_AG, B and C subtype-specific envelope sequences from Northern India and their predicted co-receptor usage

HIV-1 displays a tremendous amount of genetic diversity. The binding of the HIV-1 to host cells is mediated by envelope glycoprotein. When the HIV-1 envelope protein binds to its primary receptor CD4, it undergoes conformational changes and it then binds to one of the coreceptors (chemokine receptor CCR5, CXCR4 or others) via its V3 loop. This tri-molecular interaction leads to the viral membrane fusion [1]. HIV-1 envelope is composed of relatively conserved (C1 to C5) and variable regions (V1 to V5). The V3 region elicits neutralizing antibodies and also govern co-receptor usage [1,2]. Replacements in the V3 region with basic amino acids are associated with CXCR4 usage [2,3]. Subtypes A and C usually contain a highly conserved GPGQ amino acid motif, while GPGR is the predominant motif in the V3 loop of subtype B envelopes [4,5]. Mutational patterns in the V3 loop region are likely to be of clinical significance as they can influence their susceptibility to known CCR5 inhibitors. Although all HIV-1 genetic subtypes originated in Africa, it is not fully understood how certain subtypes dominate different regions of the world. For e.g. subtype B predominates in US and UK but subtype C is predominant in India, some parts of Asia and Africa [6].It is fairly well established that HIV-1 that uses CCR5 chemokine receptor (R5-tropic) is transmitted preferentially than the ones that use CXCR4 chemokine receptor [7]. Individuals with a 32 bp deletion in the CCR5 open reading frame (ORF) are largely protected against HIV-1 infection [7-9]. Approximately 50% of HIV-1 subtype B infected individuals show HIV-1 co-receptor switch from CCR5 to CXCR4 which is associated with rapid progression of HIV/AIDS [10]. This is observed mainly in US and UK where subtype B predominates. However, in India, where subtype C predominates, the coreceptor switch has not been observed [11]. Replacements of charged amino acids within the V3 region are known to alter the co-receptor usage [2,3,12]. Gene