Speaker
Description
Antibody (Ab) accessible sites at the surface of Env include the most variable HIV-1 sites. Different patterns of Ab recognition and neutralization are observed within and between HIV-1 clades. Predicting the functional effect of epitope diversity on Ab sensitivity is important for designing population-specific prophylactic strategies. We developed a statistical framework that incorporates sequence diversity and epitope:Ab interactions to define the functional epitope space for five broadly neutralizing Abs (bnAbs) across HIV-1 clades.
To define the epitope space for each bnAb, we first identified reference sequences that were predicted to be sensitive to the bnAb as defined by low epitope distances (a correlate of protection in the Antibody Mediated Prevention trial). We used area under the receiver operator characteristic curve for epitope distance as a function of divergence from reference sequences at each epitope site to assign impact scores to each site. We computed a principal component (PC) analysis on the distance matrix of epitopes that weighted sites based on their impact score. We calculated the distance in PC space, $\delta$, between each sequence and its nearest reference sequence.
We analyzed 10-1074 epitope (V3 glycan) space for 971 Env sequences with corresponding 10-1074 IC$_{50}$ data from the CATNAP database to validate inferences from this method. We showed that epitopes with and without known resistance mutations occupied significantly different regions of PC space (Kolmogorov-Smirnov test, P<0.01) and that $\delta$ correlated positively with IC$_{50}$ values ($\rho$=0.88).
We then analyzed epitope space for four additional representative bnAbs targeting the CD4 binding site (VRC01), gp120/gp41 interface (8ANC195), fusion peptide (PGT151), and V2 apex (VRC26.25) for 2813 Env sequences from five clades sampled between 2010-2023 and downloaded from the Los Alamos National Laboratory HIV database.
Our method maps bnAb epitope functional diversity to rationally narrow the HIV-1 space to be integrated in a vaccine candidate.
The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, the Department of Health and Human Services, or HJF.
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