Association of mutations in V3/C3 domain with enhanced sensitivity of HIV-1 clade C primary envelopes to autologous broadly neutralizing plasma antibodies.

Suprit Deshpande,Bimal K Chakrabarti,Wayne C Koff,Jayanta Bhattacharya,Aylur K Srikrishnan,Shilpa Patil,Tripti Shrivastava,Kailapuri G Murugavel,Rajesh Kumar

doi:10.1186/s12977-016-0273-x

Abstract

BackgroundBroadly neutralizing antibodies to HIV-1 elicited in infected individuals evolves through shifts in their molecular specificities to viral envelope (Env) in the disease course. Recently, we showed that resistance of circulating HIV-1 clade C to the autologous plasma obtained from one Indian elite neutralizer is associated with mutations in V1 loop. In the present study, we examined the genetic attributes associated with exceptional sensitivity of pseudoviruses expressing an env gene obtained from the follow up visit contemporaneous plasma of the same donor.ResultsExamination of chimeric autologous Envs, we found that enhanced neutralization sensitivity is associated with mutations in the V3/C3 region. A positive association between V3/C3 mutation mediated enhanced autologous neutralization of autologous viruses with their sensitivity to both neutralizing and non-neutralizing monoclonal antibodies was found. Interestingly, we found that depletion of autologous plasma with trimeric and monomeric Envs conferred the sensitive Env with resistance indicating that mutations in V3/C3 region altered Env conformation towards optimal exposure of epitopes targeted by the neutralizing and non-neutralizing antibodies.ConclusionIn summary, we found distinct vulnerabilities associated with evasion of circulating viruses to broadly neutralizing antibodies mounted in an Indian elite neutralizer.

Highlights

Neutralizing antibodies to Human Immunodeficiency Virus Type 1 (HIV-1) elicited in infected individuals evolves through shifts in their molecular specificities to viral envelope (Env) in the disease course
We examined an HIV-1 clade C Env (HVTRPG80v2.eJ7) obtained from the follow up plasma of the same donor (G37080) that significantly differed in its sensitivity to the contemporaneous autologous plasma antibodies compared to the two contemporaneous resistant Envs (HVTR-PG80v2.eJ38 and HVTR-PG80v2.eJ41)
An HIV‐1 clade C Env obtained from broadly neutralizing plasma showed exceptional degree of sensitivity to contemporaneous and retrospective autologous plasma antibodies We recently reported [13] pseudoviruses expressing env genes obtained from follow up plasma of an Indian elite neutralizer (G37080) those were found to be resistant to their contemporaneous autologous plasma antibodies

Summary

Introduction

Neutralizing antibodies to HIV-1 elicited in infected individuals evolves through shifts in their molecular specificities to viral envelope (Env) in the disease course. We showed that resistance of circulating HIV-1 clade C to the autologous plasma obtained from one Indian elite neutralizer is associated with mutations in V1 loop. We examined the genetic attributes associated with exceptional sensitivity of pseudoviruses expressing an env gene obtained from the follow up visit contemporaneous plasma of the same donor. In an IAVI Protocol G study, by examining Envs obtained from broadly cross neutralizing (BCN) plasma of an elite neutralizer (G37080) collected at two different time points and spaced between 8 months, we showed that mutations in the V1 loop was associated with autologous neutralization escape [13]. We examined an HIV-1 clade C Env (HVTRPG80v2.eJ7) obtained from the follow up plasma of the same donor (G37080) that significantly differed in its sensitivity to the contemporaneous autologous plasma antibodies compared to the two contemporaneous resistant Envs (HVTR-PG80v2.eJ38 and HVTR-PG80v2.eJ41). The enhanced sensitivity of pseudoviruses expressing HVTRPG80v2.eJ7 Env to the contemporaneous autologous broadly neutralizing plasma antibodies was found to be associated with mutations in the V3/C3 region and exposure of discontinuous epitopes targeted by neutralizing antibodies with multiple specificities

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Conclusion