Abstract
Various HIV-1 env genetic and biochemical features impact the elicitation of cross-reactive neutralizing antibodies in natural infections. Thus, we aimed to investigate cross-neutralizing antibodies in individuals infected with HIV-1 env subtypes B, F1, C or the B/Bbr variant as well as env characteristics. Therefore, plasma samples from Brazilian chronically HIV-1 infected individuals were submitted to the TZM-bl neutralization assay. We also analyzed putative N-glycosylation sites (PNGLs) and the size of gp120 variable domains in the context of HIV-1 subtypes prevalent in Brazil. We observed a greater breadth and potency of the anti-Env neutralizing response in individuals infected with the F1 or B HIV-1 subtypes compared with the C subtype and the variant B/Bbr. We observed greater V1 B/Bbr and smaller V4 F1 than those of other subtypes (p<0.005), however neither was there a correlation verified between the variable region length and neutralization potency, nor between PNLG and HIV-1 subtypes. The enrichment of W at top of V3 loop in weak neutralizing response viruses and the P in viruses with higher neutralization susceptibility was statistically significant (p = 0.013). Some other signatures sites were associated to HIV-1 subtype-specific F1 and B/Bbr samples might influence in the distinct neutralizing response. These results indicate that a single amino acid substitution may lead to a distinct conformational exposure or load in the association domain of the trimer of gp120 and interfere with the induction power of the neutralizing response, which affects the sensitivity of the neutralizing antibody and has significant implications for vaccine design.
Highlights
A vaccine that aims to elicit strong HIV neutralizing antibodies must overcome their genetic variability at least at the antigenic level
The Brazilian psVs were inhibited by all monoclonal antibodies (mAbs) and presented reduced IC50 geometric means when compared to psVB and psVC (Table 1). sCD4 neutralized all of the studied psVs, and mAbs 2F5, and CH01 were able to neutralize almost all of the psVs with the exception of the psVC and psVB, respectively
We evaluated the neutralization breadth and potency of plasma samples from HIV-1-infected Brazilian individuals using a representative panel of psVs and attempted to correlate the antibody response to the genetic and biochemical characteristics of HIV-1 subtypes
Summary
A vaccine that aims to elicit strong HIV neutralizing antibodies (nAb) must overcome their genetic variability at least at the antigenic level. Several studies have reported that antibodies from plasma obtained during chronic HIV-1 infection could potently neutralize primary isolates of HIV-1 and were able to neutralize genetically diverse and distinct HIV-1 strains [4,5,6,7,8] These nAb primarily recognize five different epitopes on Env, including the CD4 biding site (CD4bs), V1/V2 loop, V3 loop, interface gp120/gp and the membrane-proximal external region (MPER) on gp41 [9,10,11,12]. In response to the constant HIV-1 genetic evolution, the epitope specificity of the nAb that is gradually developed during infection influences the breadth of the nAb responses [13,14] Some viral features, such as variable loop lengths and the number of glycosylation motifs, are associated with the neutralization breadth [3,15,16,17]. The characterization of neutralization specificities for distinct subtypes is a difficult but critical process to accumulate knowledge and develop a successful vaccine
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