CD4 independence of simian immunodeficiency virus Envs is associated with macrophage tropism, neutralization sensitivity, and attenuated pathogenicity

Bridget A. Puffer, Stefan Pöhlmann, Aimee L. Edinger, Dan Carlin, Melissa D. Sanchez, Julie Reitter, Debbie D. Watry, Howard S. Fox, Ronald Charles Desrosiers, Robert W. Doms

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2595-2605
Number of pages11
JournalJournal of Virology
Volume76
Issue number6
DOIs
StatePublished - 2002
Externally publishedYes

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Simian immunodeficiency virus
Simian Immunodeficiency Virus
tropisms
Tropism
neutralization
Virulence
tropics
macrophages
pathogenicity
Macrophages
Humoral Immunity
Viruses
Antibodies
humoral immunity
viruses
antibodies
Virus Attachment
Membrane Fusion
Glycosylation
glycosylation

ASJC Scopus subject areas

  • Immunology

Cite this

CD4 independence of simian immunodeficiency virus Envs is associated with macrophage tropism, neutralization sensitivity, and attenuated pathogenicity. / Puffer, Bridget A.; Pöhlmann, Stefan; Edinger, Aimee L.; Carlin, Dan; Sanchez, Melissa D.; Reitter, Julie; Watry, Debbie D.; Fox, Howard S.; Desrosiers, Ronald Charles; Doms, Robert W.

In: Journal of Virology, Vol. 76, No. 6, 2002, p. 2595-2605.

Research output: Contribution to journalArticle

Puffer, Bridget A. ; Pöhlmann, Stefan ; Edinger, Aimee L. ; Carlin, Dan ; Sanchez, Melissa D. ; Reitter, Julie ; Watry, Debbie D. ; Fox, Howard S. ; Desrosiers, Ronald Charles ; Doms, Robert W. / CD4 independence of simian immunodeficiency virus Envs is associated with macrophage tropism, neutralization sensitivity, and attenuated pathogenicity. In: Journal of Virology. 2002 ; Vol. 76, No. 6. pp. 2595-2605.
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T1 - CD4 independence of simian immunodeficiency virus Envs is associated with macrophage tropism, neutralization sensitivity, and attenuated pathogenicity

AU - Puffer, Bridget A.

AU - Pöhlmann, Stefan

AU - Edinger, Aimee L.

AU - Carlin, Dan

AU - Sanchez, Melissa D.

AU - Reitter, Julie

AU - Watry, Debbie D.

AU - Fox, Howard S.

AU - Desrosiers, Ronald Charles

AU - Doms, Robert W.

PY - 2002

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AB - 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.

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