Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities

Abstract

Background The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and a few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. Results We found significant variations in the susceptibility of Indian clade C to these four bnAbs. These variations were found to be distinct to that observed in African subtype C based on the existing datasets and concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed over time with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999 to 2016. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber (http://www.hiv.lanl.gov), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage. Conclusions Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrant the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.

Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials

“…Importantly, these recent viruses displayed increased neutralization resistance to CAP256.25 (p = 0.03) and VRC07-523LS (p = 0.02) compared to the historical 200 Clade C Panel. These results are consistent with data from Indian Clade C viruses showing resistance to CAP256.25 at a population level over time [ 24 ]. Rademeyer et al also observed that viruses became increasingly resistant to VRC01 (CD4bs), PG9 (V2-binding) and 4E10 (MPER/gp41-binding) over a 13-year period [ 6 ].…”

“…Rademeyer et al also observed that viruses became increasingly resistant to VRC01 (CD4bs), PG9 (V2-binding) and 4E10 (MPER/gp41-binding) over a 13-year period [ 6 ]. While a significant decrease in sensitivity to VRC01 was not observed in our study, we did note a trend towards resistance to VRC01 and 3BNC117, which share some signature contact sites [ 25 – 28 ], suggesting a shift in general resistance to CD4bs antibodies over time [ 6 , 24 ]. The increased resistance to CD4bs and V2 bnAbs suggests the possibility that similar responses are common in HIV infection and are responsible for applying selective pressure to viral populations.…”