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Evolution of cross-neutralizing antibodies and mapping epitope specificity in plasma of chronic HIV-1-infected antiretroviral therapy-naïve children from India.

Evolution of cross-neutralizing antibodies and mapping epitope specificity in plasma of chronic HIV-1-infected antiretroviral therapy-naïve children from India.
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Makhdoomi MA, Khan L, Kumar S, Aggarwal H, Singh R, Lodha R, Singla M, Das BK, Kabra SK, Luthra K,


Makhdoomi MA, Khan L, Kumar S, Aggarwal H, Singh R, Lodha R, Singla M, Das BK, Kabra SK, Luthra K, (click to view)

Makhdoomi MA, Khan L, Kumar S, Aggarwal H, Singh R, Lodha R, Singla M, Das BK, Kabra SK, Luthra K,

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The Journal of general virology 2017 07 12() doi 10.1099/jgv.0.000824

Abstract

Delineating the factors leading to the development of broadly neutralizing antibodies (bnAbs) during natural HIV-1 infection and dissecting their epitope specificities generates useful information for vaccine design. This is the first longitudinal study to assess the plasma-neutralizing antibody response and neutralizing determinants in HIV-1-infected children from India. We enrolled 26 and followed up 20 antiretroviral therapy (ART)-naïve, asymptomatic, chronic HIV-1-infected children. Five (19.2 %) baseline and 10 (50 %) follow-up plasma samples neutralized ≥50 % of subtypes A, B and C tier 2 viruses at an ID50 titre ≥150. A modest improvement in neutralization breadth and potency was observed with time. At baseline, subtype C-specific neutralization predominated (P=0.026); interestingly, follow-up samples exhibited cross-neutralizing activity. Epitope mapping revealed V3C reactive antibodies with significantly increased Max50 binding titres in follow-up samples from five infected children; patient #4’s plasma antibodies exhibited V3-directed neutralization. A salient observation was the presence of CD4 binding site (CD4bs)-specific NAbs in patient #18 that improved with time (1.76-fold). The RSC3 wild-type (RSC3WT) protein-depleted plasma eluate of patient #18 demonstrated a more than 50% ID50 decrease in neutralization capacity against five HIV-1 pseudoviruses. Further, the presence of CD4bs-neutralizing determinants in patient #18’s plasma was confirmed by the neutralizing activity demonstrated by the CD4bs-directed IgG fraction purified from this plasma, and competition with sCD4 against JRFLgp120, identifying this paediatric donor as a potential candidate for the isolation of CD4bs-directed bnAbs. Overall, we observed a relative increase in plasma-neutralizing activity with time in HIV-1-infected children, which suggests that the bnAbs evolve.

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