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Journal of Virology, March 2002, p. 2595-2605, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2595-2605.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

CD4 Independence of Simian Immunodeficiency Virus Envs Is Associated with Macrophage Tropism, Neutralization Sensitivity, and Attenuated Pathogenicity

Bridget A. Puffer,1 Stefan Pöhlmann,1 Aimee L. Edinger,2 Dan Carlin,1 Melissa D. Sanchez,1 Julie Reitter,3 Debbie D. Watry,4 Howard S. Fox,4 Ronald C. Desrosiers,3 and Robert W. Doms1*

Department of Microbiology,1 Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104,2 New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102,3 Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 920374

Received 27 June 2001/ Accepted 5 December 2001

To investigate the basis for envelope (Env) determinants influencing simian immunodeficiency virus (SIV) tropism, we studied a number of Envs that are closely related to that of SIVmac239, a pathogenic, T-tropic virus that is neutralization resistant. The Envs from macrophage-tropic (M-tropic) virus strains SIVmac316, 1A11, 17E-Fr, and 1100 facilitated infection of CCR5-positive, CD4-negative cells. In contrast, the SIVmac239 Env was strictly dependent upon the presence of CD4 for membrane fusion. We also found that the Envs from M-tropic virus strains, which are less pathogenic in vivo, were very sensitive to antibody-mediated neutralization. Antibodies to the V3-loop, as well as antibodies that block SIV gp120 binding to CCR5, efficiently neutralized CD4-independent, M-tropic Envs but not the 239 Env. However, triggering the 239 Env with soluble CD4, presumably resulting in exposure of the CCR5 binding site, made it as neutralization sensitive as the M-tropic Envs. In addition, mutations of N-linked glycosylation sites in the V1/V2 region, previously shown to enhance antigenicity and immunogenicity, made the 239 Env partially CD4 independent. These findings indicate that Env-based determinants of M tropism of these strains are generally associated with decreased dependence on CD4 for entry into cells. Furthermore, CD4 independence and M tropism are also associated with neutralization sensitivity and reduced pathogenicity, suggesting that the humoral immune response may exert strong selective pressure against CD4-independent M-tropic SIVmac strains. Finally, genetic modification of viral Envs to enhance CD4 independence may also result in improved humoral immune responses.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania, 225 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104. Phone: (215) 898-0890. Fax: (215) 573-9557. E-mail: doms{at}mail.med.upenn.edu.

Journal of Virology, March 2002, p. 2595-2605, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2595-2605.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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