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17 Immunotype and CD4 Independence of HIV-1 Envelope with Broad Primary Virus Neutralizing Cross-Reactivity Is Determined by Unusual V3 Sequence
P. F. Zhang*1, P. Bouma1, S. Zolla-Pazner3, J. Margolik2, J. Robinson4, and G. Quinnan1
1Uniformed Services Univ. of the Hlth. Sci., Bethesda, MD, USA; 2Johns Hopkins Univ., Baltimore, MD, USA; 3New York Univ., New York, USA; and 4Tulane Univ., New Orleans, LA, USA
Background: The reference serum HNS2 and the R2 strain HIV-1 envelope gene derived from the same donor display broadly cross-reactive neutralization. Studies were conducted to evaluate the relationship between neutralization sensitivity and other characteristics of this envelope.
Methods: Neutralization of viruses pseudotyped with the R2 envelope or with envelopes from other primary and laboratory-adapted strains of HIV-1 was evaluated. Neutralization assays included use of various monoclonal antibodies (Mab) and soluble CD4 (sCD4). Infections were performed in HOS cells expressing CCR5 or CXCR4, with or without CD4, as appropriate.
Results: R2 virus was moderately sensitive to neutralization by Mab against apical V3 (e.g., 19b), CD4bs (e.g., 15e), and CD4i (e.g., 17b) epitopes, and sCD4. An unusual PM sequence just proximal to the V3 apex substantially affected neutralization of R2 by human sera, the 19b, 15e, and 17b Mab, and sCD4. This PM sequence also enhanced sensitivity to neutralization of 3 other primary envelopes by HNS2 and the Mabs 19b and 17b. The sensitivity of 1 of the clones to neutralization by the Mab 15e and by sCD4 was enhanced by sCD4. The infectivity of the R2 clone and all 3 of the other primary envelopes for HOS CD4+CCR5+ cells was enhanced by the 313-4PM mutation, whereas R2 and 1 of these other envelopes were made infectious for HOS CD4-CCR5+ cells by the mutation.
Conclusions: The immunotype of clone R2 (sensitivity to cross-reactive human serum neutralization and intermediate global neutralization sensitivity) and its CD4-independent infectivity phenotype are determined by its unusual V3 sequence. Enhanced infection competence may relate to this immunotype and to R2 immunogenicity and may serve to maintain the immunotype in vivo in spite of immune selection.
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