Abstract
Evolving diversity in globally circulating HIV-1 subtypes presents a formidable challenge in defining and developing neutralizing antibodies for prevention and treatment. HIV-1 subtype C is responsible for majority of global HIV-1 infections. In the present study, we examined the diversity in genetic signatures and attributes that differentiate region-specific HIV-1 subtype C gp120 sequences associated with virus neutralization outcomes to key bnAbs having distinct epitope specificities. A total of 1814 full length HIV-1 subtype C gp120 sequence from 37 countries were retrieved from Los Alamos National Laboratory HIV database (www.hiv.lanl.gov). The amino acid sequences were assessed for their phylogenetic association, variable loop lengths and prevalence of potential N-linked glycosylation sites (pNLGS). Responses of these sequences to bnAbs were predicted with a machine learning algorithm ‘bNAb-ReP’ and compared with those reported in the CATNAP database. Subtype C sequences from Asian countries including India differed phylogenetically when compared with that from African countries. Variable loop lengths and charges within Indian and African clusters were also found to be distinct from each other, specifically for V1, V2 and V4 loops. Pairwise analyses at each of the 25 pNLG sites indicated distinct country specific profiles. Highly significant differences (p<0.001***) were observed in prevalence of four pNLGS (N130, N295, N392 and N448) between South Africa and India, having most disease burden associated with subtype C. Our findings highlight that distinctly evolving clusters within global intra-subtype C gp120 sequences are likely to influence the disparate region-specific sensitivity of circulating HIV-1 subtype C to bnAbs.
Highlights
The extraordinary diversity of env targeting neutralizing antibodies is a barrier to achieving the desired vaccine-induced and antibody-mediated protection
The trimeric envelope glycoprotein (Env) glycoproteins on the virus surface are the most diverse of all proteins encoded by HIV-1; which differs by greater than 20% of amino acids between matched subtypes [10,11,12,13,14] and which continues to diversify at a population level [14,15,16,17]
While Broadly neutralizing antibodies (bnAbs) target both surface gp120 and membrane proximal external region (MPER) of gp41, gp120 exhibits extraordinary sequence divergence compared to gp41 MPER and variation in this region is believed to represent distinct genetic subtypes, or clades, which are prevalent in distinct geographic regions [18, 19]
Summary
The extraordinary diversity of env targeting neutralizing antibodies is a barrier to achieving the desired vaccine-induced and antibody-mediated protection. The trimeric Env glycoproteins on the virus surface are the most diverse of all proteins encoded by HIV-1; which differs by greater than 20% of amino acids between matched subtypes [10,11,12,13,14] and which continues to diversify at a population level [14,15,16,17]. This has been substantiated by observation that several epitopes that are targeted by different bnAbs have been found to vary over time [15]. We examined the variation in signature sequences, loop length, N-linked glycosylation and key epitopes within the existing globally circulating HIV-1 subtype C gp120 targeted by potent bnAbs and predicted their impact on virus neutralization
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