In HIV infection, only 10-30% of the individuals are able to generate broadly neutralizing antibody response (bnAbs).Development of bnAb response was significantly associated with duration of infection, high viral load and low CD4 counts among typical progressors. Conversely, HIV-1 viremic non-progressors are individuals who maintain higher CD4 counts with moderate viral load without asymptomatic for > 7 yrs of infection. However, bnAb response has not been described among HIV-1 viremic non-progressors
In this study, plasma samples from a cohort of 90 ART-Naive HIV-1 infected individuals with various disease progression stages were tested against Tier-2 global virus panel (n=11) includes subtype A, B C, G, AC, BC & AE. The cohort includes viremic controllers, viremic non-progressors and typical progressors. The epitope mapping by ELISAs, neutralization of V2 (N160A &R166A) &V3 (N301A &N332A) point mutants and protein competition neutralization assay with MPER &RSC3 antigens. Samples that are able to neutralize >50% of virus with ID[50] >100 (moderate neutralization), were then tested against an extended virus panel (n=19) to find Elite neutralization. Elite neutralizers are those able to neutralize >75% of viruses tested with ID[50] >100 and geometric mean ID[50] > 500.
Through screening of 90 plasma samples we observed moderate neutralization among 28 samples (Table: 1). Neutralization potency among viremic non-progressors were significantly higher than typical progressors (p=0.043). Remarkably, we were able to identify 4 elite neutralizers with geometric mean ID[50] titer between 500 and 700 and three of them were viremic non-progressors. Epitope mapping of those elite neutralizers were not specific to known targets like V2, V3, CD4bs and MPER region. Interestingly, the top most elite neutralizer has neutralized N301A mutant virus with 2.0 fold greater than the wild type. When assessed its CD4bs neutralization activity by treating with RSC3 protein, there was 1.5 fold drops in the ID[50] titer to the untreated plasma.
These results demonstrate that viremic non-progressors develop bnAb response and it suggests that provision of CD4 helper T cells is critical for formation of functional germinal centre. This bnAb response was associated with the presence of CD4bs Abs and it is due to viral escape in N301 glycan of V3 region which may expose occluded conserved epitope that facilitating the development of breath among elite neutralizers.