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Comparative evaluation of trimeric envelope glycoproteins derived from subtype C and B HIV-1 R5 isolates.

Srivastava, Indresh K and Kan, Elaine and Sun, Yide and Sharma, Victoria A and Cisto, Jimna and Burke, Brian and Lian, Ying and Hilt, Susan and Biron, Zohar and Hartog, Karin and Stamatatos, Leonidas and Diaz-Avalos, Ruben and Cheng, R Holland and Ulmer, Jeffrey and Barnett, Susan W (2008) Comparative evaluation of trimeric envelope glycoproteins derived from subtype C and B HIV-1 R5 isolates. Virology, 372 (2). pp. 273-290. ISSN 0042-6822

Abstract

We previously reported that an envelope (Env) glycoprotein immunogen (o-gp140DeltaV2SF162) containing a partial deletion in the second variable loop (V2) derived from the R5-tropic HIV-1 isolate SF162 partially protected vaccinated rhesus macaques against pathogenic SHIV(SF162P4) virus. Extending our studies to subtype C isolate TV1, we have purified o-gp140DeltaV2TV1 (subtype C DeltaV2 trimer) to homogeneity, performed glycosylation analysis, and determined its ability to bind CD4, as well as a panel of well-characterized neutralizing monoclonal antibodies (mAb). In general, critical epitopes are preserved on the subtype C DeltaV2 trimer; however, we did not observe significant binding for the b12 mAb. The molecular mass of subtype C DeltaV2 trimer was found to be 450 kDa, and the hydrodynamic radius was found to be 10.87 nm. Our data suggest that subtype C DeltaV2 trimer binds to CD4 with an affinity comparable to o-gp140DeltaV2SF162 (subtype B DeltaV2 trimer). Using isothermal titration calorimetric (ITC) analysis, we demonstrated that all three CD4 binding sites (CD4-BS) in both subtype C and B trimers are exposed and accessible. However, compared to subtype B trimer, the three CD4-BS in subtype C trimer have different affinities for CD4, suggesting a cooperativity of CD4 binding in subtype C trimer but not in subtype B trimer. Negative staining electron microscopy of the subtype C DeltaV2 trimer has demonstrated that it is in fact a trimer. These results highlight the importance of studying subtype C Env, and also of developing appropriate subtype C-specific reagents that may be used for better immunological characterization of subtype C Env for developing an AIDS vaccine.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: HIV; Trimer; Subtype C; CD4; Neutralizing antibodies; ITC
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Date Deposited: 14 Dec 2009 13:51
Last Modified: 14 Dec 2009 13:51
URI: https://oak.novartis.com/id/eprint/940

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