A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding
ABSTRACT The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp120 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp120 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections.
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- "Exclusion of amino acid positions 11 and 25 decreased the accuracy by approximately 5%, with position 11 contributing the majority of the lost information  Overall, these results suggest that all amino acids within the V3 region contribute to co-receptor usage selection. In addition, further studies involving HIV-1 envelope mutagenesis have indicated that amino acid residues outside the V3 loop region could influence the structure of gp120 induced by CD4 binding, which is critical for co-receptor binding and viral tropism  . "
ABSTRACT: The evolution of human immunodeficiency virus type 1 (HIV-1) with respect to co-receptor utilization has been shown to be relevant to HIV-1 pathogenesis and disease.The CCR5-utilizing (R5) virus has been shown to be important in the very early stages of transmission and highly prevalent during asymptomatic infection and chronic disease.In addition, the R5 virus has been proposed to be involved in neuroinvasion and central nervous system (CNS) disease.In contrast, the CXCR4-utilizing (X4) virus is more prevalent during the course of disease progression and concurrent with the loss of CD4+Tcells.The dual-tropic virus is able to utilize both co-receptors (CXCR4 and CCR5) and has been thought to represent an intermediate transitional virus that possesses properties of both X4 and R5 viruses that can be encountered at many stages of disease. The use of computationaltools and bioinformatic approaches in the prediction of HIV-1 co-receptor usage has been growing in importance with respect to understanding HIV-1 pathogenesis and disease, developingdiagnostic tools,and improving the efficacy of therapeutic strategies focused on blocking viral entry.Current strategies have enhanced the sensitivity, specificity, and reproducibility relative to the prediction of co-receptor use; however, these technologies need to be improved with respect to their efficient and accurate use across the HIV-1 subtypes. The most effective approach may center on the combined use of different algorithms involving sequences within and outside of the env-V3 loop. This review focuses on the HIV-1 entry process and on co-receptor utilization, including bioinformatic tools utilized in the prediction of co-receptor usage. It also provides novel preliminary analyses for enabling identification of linkages between amino acids in V3 with other components of the HIV-1 genome and demonstrates that these linkages are different between X4 and R5 viruses.Current HIV Research 05/2014; DOI:10.2174/1570162X12666140526121746 · 2.14 Impact Factor
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- "This additional inhibitory function of V2 mAbs was not measured in the neutralization assay used in the study because the TZM-bl target cells do not express α4β7 integrin. Thus, in the TZM-bl cell assay, the anti-V2 mAbs mediate neutralization by affecting the co-receptor binding site which is formed by the stem of the V1V2, V3 and the bridging sheet upon virus binding to the CD4 receptor (Kwong et al., 1998; Rizzuto et al., 1998; Wu et al., 1996). Evidently, this mechanism of neutralization, which has a post-binding character exhibited after the virus binds to cellular CD4, is responsible for the neutralizing activity of anti-V2 mAbs in the TZM-bl cell assay. "
ABSTRACT: The recent analysis of the first successful RV144 vaccine trial revealed that a high titer of plasma anti-V2 antibodies (Abs) correlated with a decreased risk of HIV-1 infection in vaccine recipients. To understand the mechanism of immune correlates, we studied seven anti-V2 monoclonal Abs (mAbs) developed from HIV-1 infected individuals. The V2 mAbs target conserved epitopes, including the binding site for α4β7 integrin, and are broadly cross-reactive with various gp120 proteins. Preferential usage of the VH1-69 gene by V2 mAbs may depend on selection by the same antigenic structure. Six of seven V2 mAbs weakly neutralized four to eight of the 41 pseudoviruses tested and resistance to neutralization was correlated with longer V2 domains. The data suggest the presence of shared, conserved structural elements in the V2 loop, and these can be used in the design of vaccine immunogens inducing broadly reactive Abs with anti-viral activities.Virology 03/2012; 427(2):198-207. DOI:10.1016/j.virol.2012.02.003 · 3.28 Impact Factor
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- "H77.39 and J6.36) mapping to HVR1 or contiguous regions, we did not observe this effect for weakly neutralizing MAbs (H77.31 and J6.27) that localize to the CD81 binding region. The failure to observe enhanced inhibitory activity by E2-specific MAbs that interfere with CD81 binding may reflect a requirement for more significant structural shifts for complete epitope exposure, analogous to the those required to reveal the CCR5 binding epitope on HIV gp120 (Kwong et al., 1998; Rizzuto et al., 1998). Indeed, previous studies have demonstrated that anti-CD81 antibodies inhibit infection at a postattachment step, indicating that CD81 is not completely engaged by the virus directly after attachment (Bertaux and Dragic, 2006; Haberstroh et al., 2008; Sabo et al., 2011). "
ABSTRACT: A recent study with flaviviruses suggested that structural dynamics of the virion impact antibody neutralization via exposure of ostensibly cryptic epitopes. To determine whether this holds true for the distantly related hepatitis C virus (HCV), whose neutralizing epitopes may be obscured by a glycan shield, apolipoprotein interactions, and the hypervariable region on the E2 envelope protein, we assessed how time and temperature of pre-incubation altered monoclonal antibody (MAb) neutralization of HCV. Notably, several MAbs showed increased inhibitory activity when pre-binding was performed at 37°C or after longer pre-incubation periods, and a corresponding loss-of-neutralization was observed when pre-binding was performed at 4°C. A similar profile of changes was observed with acute and chronic phase sera from HCV-infected patients. Our data suggest that time and temperature of incubation modulate epitope exposure on the conformational ensembles of HCV virions and thus, alter the potency of antibody neutralization.Virology 11/2011; 422(2):174-84. DOI:10.1016/j.virol.2011.10.023 · 3.28 Impact Factor