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Journal of Virology, January 2008, p. 903-916, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01444-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Subtype-Specific Conformational Differences within the V3 Region of Subtype B and Subtype C Human Immunodeficiency Virus Type 1 Env Proteins{triangledown}

Milloni B. Patel, Noah G. Hoffman,{dagger} and Ronald Swanstrom*

Department of Microbiology and Immunology and Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295

Received 3 July 2007/ Accepted 31 October 2007

The V3 region of the human immunodeficiency virus type 1 gp120 Env protein is a key domain in Env due to its role in interacting with the coreceptors CCR5 and CXCR4. We examined potential subtype-specific V3 region differences by comparing patterns of amino acid variability and probing for subtype-specific structures using 11 anti-V3 monoclonal antibodies (V3 MAbs). Differences between the subtypes in patterns of variability were most evident in the stem and turn regions of V3 (positions 9 to 24), with the two subtypes being very similar in the base region. The characteristics of the binding of V3 MAbs to Env proteins of the subtype B virus JR-FL and the subtype C virus BR025 suggested three patterns, as each group of MAbs recognized a specific conformation- or sequence-based epitope. Viruses pseudotyped with Env from JR-FL and BR025 were resistant to neutralization by the V3 MAbs, although the replacement of the Env V3 region of the SF162 virus with the JR-FL V3 created a pseudotyped virus that was hypersensitive to neutralization. A single mutation in V3 (H13R) made this chimeric Env selectively resistant to one group of V3 MAbs, consistent with the mAb binding properties. We hypothesize that there are intrinsic differences in V3 conformation between subtype B and subtype C that are localized to the stem and turn regions and that these differences have two important biological consequences: first, subtype B and subtype C V3 regions can have subtype-specific epitopes that will inherently limit antibody cross-reactivity, and second, V3 conformational differences may potentiate the frequent evolution of R5- into X4-tropic variants of subtype B but limit subtype C virus from using the same mechanism to evolve X4-tropic variants as efficiently.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB #7295, Chapel Hill, NC 27599-7295. Phone: (919) 966 5710. Fax: (919) 966 8212. E-mail: risunc{at}med.unc.edu

{triangledown} Published ahead of print on 14 November 2007.

{dagger} Present address: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195-7110.

Journal of Virology, January 2008, p. 903-916, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01444-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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