Virology. 2014 Aug;462-463:266-72.

Determinants in V2C2 region of HIV-1 clade C primary envelopes conferred altered neutralization susceptibilities to IgG1b12 and PG9 monoclonal antibodies in a context-dependent manner.

Patil S1, Choudhary I2, Chaudhary NK1, Ringe R2, Bansal M1, Shukla BN1, Boliar S1, Chakrabarti BK1, Bhattacharya J3.

  • 1HIV Vaccine Translational Research Laboratory, THSTI-IAVI HIV Vaccine Design Program, Translational Health Science and Technology Institute, 450, Udyog Vihar, Phase-III, Gurgaon 122016, Haryana, India.
  • 2National AIDS Research Institute, Pune, Maharashtra, India.
  • 3HIV Vaccine Translational Research Laboratory, THSTI-IAVI HIV Vaccine Design Program, Translational Health Science and Technology Institute, 450, Udyog Vihar, Phase-III, Gurgaon 122016, Haryana, India. Electronic address: JBhattacharya@iavi.org.

 

ABSTRACT:

In the present study by examining pseudoviruses expressing patient chimeric envelopes (Envs) made between an IgG1b12 (b12)-sensitive (2-5.J3) and a b12-resistant (4.J22) HIV-1 clade C envelope, we identified determinants in the V2C2 region that governed susceptibility to b12 monoclonal antibody, but not to other CD4 binding site antibodies. Interestingly, when the V2C2 sequence of the 2-5.J3 Env was transferred to other b12-resistant primary clade C Envs, their susceptibility to b12 varied, indicating that this effect was context dependent. In addition, we identified determinants within the V2 region in the b12-resistant envelope that significantly modulated the neutralization of Env-pseudotyped viruses to PG9/PG16 MAbs. The enhanced neutralization susceptibilities of Envs to b12 and PG9 MAbs were correlated with increased exposure of their corresponding epitopes highlighting vulnerabilities in the V2C2 region that altered Env conformation necessary for the efficient accessibility of b12 and PG9 antibodies. Copyright © 2014 Elsevier Inc.

KEYWORDS: CD4bs; Clade C; Envelope; HIV-1; IgG1b12; Neutralizing antibody; PG16; PG9; VRC01

PMID: 24999839

 

SUPPLEMENT:

HIV-1 requires CD4 for entry and hence this portal remains an excellent target for design and discovery of preventive vaccines that would be able to block infection at the virus entry level. IgG1b12 is the first monoclonal antibody (mAb) identified that overlaps CD4 binding region and has been shown to effectively neutralize several virus strains (1). However, HIV-1 clade C strains grossly are ineffective for neutralization by the IgG1b12 antibody. We earlier demonstrated that HIV-1 clade C envelopes (Env) obtained from an Indian patient in the disease course were unusually sensitive to IgG1b12 mAb (2). In this study, using engineered chimeric Envs and by site-directed mutagenesis, we demonstrated that V2C2 region of clade C Env altered IgG1b12 susceptibility in a context-dependent manner. In this process, we also identified minimal amino acid residues in the V2 loop that were found to modulate Env susceptibility to PG9 and PG16 mAbs that targets quaternary epitopes (QNE) in this region of envelope. For example, we demonstrated that the presence of glycan residues at the positions 186(N186) and192 (N192) significantly abrogated access of PG9/16 mAbs to the QNE in the V2 loop of the virus envelope protein. Our data suggest that the V2C2 region of the HIV-1 Env likely affect the spike apex region, which in turn influence viral Env to undergo conformational changes resulting in differential modulation of exposure of epitopes targeted by IgG1b12 mAb. Since conformational alteration is a complex phenomenon, we found this observation context dependent when tested with unrelated viral envelope proteins. Such information may explain complex nature of conformation guided exposure of epitopes vulnerable for immune evasion by HIV-1.

References:

1. Burton, D. R., J. Pyati, R. Koduri, S. J. Sharp, G. B. Thornton, P. W. Parren, L. S. Sawyer, R. M. Hendry, N. Dunlop, and P. L. Nara. 1994. Efficient neutralization of primary isolates of HIV- 1 by a recombinant human monoclonal antibody. Science 266:1024–1027.
2. Ringe, R., M. Thakar, and J. Bhattacharya. 2010. Variations in autologous neutralization and CD4 dependence of b12 resistant HIV-1 clade C env clones obtained at different time points from antiretroviral naive Indian patients with recent infection. Retrovirology 7:76.

 

WBF2

 Fig. Key investigators of the study

 

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