%0 Journal Article
%T Resistance of Subtype C HIV-1 Strains to Anti-V3 Loop Antibodies
%A David Almond
%A Chavdar Krachmarov
%A James Swetnam
%A Susan Zolla-Pazner
%A Timothy Cardozo
%J Advances in Virology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/803535
%X HIV-1¡¯s subtype C V3 loop consensus sequence exhibits increased resistance to anti-V3 antibody-mediated neutralization as compared to the subtype B consensus sequence. The dynamic 3D structure of the consensus C V3 loop crown, visualized by ab initio folding, suggested that the resistance derives from structural rigidity and non-¦Â-strand secondary protein structure in the N-terminal strand of the ¦Â-hairpin of the V3 loop crown, which is where most known anti-V3 loop antibodies bind. The observation of either rigidity or non-¦Â-strand structure in this region correlated with observed resistance to antibody-mediated neutralization in a series of chimeric pseudovirus (psV) mutants. The results suggest the presence of an epitope-independent, neutralization-relevant structural difference in the antibody-targeted region of the V3 loop crown between subtype C and subtype B, a difference that we hypothesize may contribute to the divergent pattern of global spread between these subtypes. As antibodies to a variable loop were recently identified as an inverse correlate of risk for HIV infection, the structure-function relationships discussed in this study may have relevance to HIV vaccine research. 1. Introduction Subtype C infections now represent the majority of HIV-1 infections worldwide [1], suggesting greater in vivo or host-pathogen fitness. By contrast, in direct in vitro competition assays, R5 subtype B isolates outcompete R5 subtype C isolates [2], suggesting greater in vitro infective fitness. Thus, more rapid in vivo spread of subtype C infections may be occurring despite an apparent greater in vitro fitness of subtype B. Differential susceptibility to human antibody-mediated neutralization could result in differing extents of global spread between different subtypes. The V3 loop is often referred to as the principal neutralizing determinant of HIV-1 viruses as several of the early and recent studies describing human antibodies that could neutralize HIV-1 were dominated by anti-V3 loop antibodies [3¨C6]. Indeed, several observations suggest a conformational or functional difference between subtype B and subtype C V3 loops [7], but the nature of the difference has not been elucidated. The V3 loop is also the site of CCR5 and CXCR4 engagement, a necessary determinant of virus entry [8¨C13]. Thus, antibody neutralization determinants and infective determinants coincide to the same location on the HIV-1 envelope glycoprotein surface, and disturbances to one are likely to affect the other. A comparison of antibody-mediated neutralizations of SF162 chimeric
%U http://www.hindawi.com/journals/av/2012/803535/