Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5

Megan E. Mefford; Kevin Kunstman; Steven M. Wolinsky; Dana Gabuzda

doi:10.1016/j.virol.2015.01.032

Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5

Megan E. Mefford, Kevin Kunstman, Steven M. Wolinsky, Dana Gabuzda^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120-CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.

Original language	English (US)
Pages (from-to)	210-222
Number of pages	13
Journal	Virology
Volume	481
DOIs	https://doi.org/10.1016/j.virol.2015.01.032
State	Published - Jul 1 2015

Funding

We thank J. Cunningham, J. Sodroski, and B. Chen for helpful discussions, R. Bosch for helpful discussions regarding statistical analysis of HIV sequences, N. Letvin for TZM-bl cells, B. Lee for Affinofile cells, and Will (Po-Jen) Yen for help with structural modeling. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID: monoclonal antibody 17b from Dr. James E. Robinson, goat anti-gp120, and TAK-779. This work was supported by NIH Grants MH83588 and MH97659 to D.G. M.E.M. was supported in part by NIH fellowship F31NS060611 . Core facilities were supported by Harvard Medical School Center for AIDS Research (CFAR) and DFCI/Harvard Cancer Center Grants P30 AI060354 and P30 CA06516 .

Keywords

Bridging sheet
CCR5
CD4
Envelope
HIV
Macrophage
Tropism
V1/V2 stem

ASJC Scopus subject areas

Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.virol.2015.01.032

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title = "Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5",

abstract = "Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120-CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.",

keywords = "Bridging sheet, CCR5, CD4, Envelope, HIV, Macrophage, Tropism, V1/V2 stem",

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AU - Gabuzda, Dana

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AB - Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120-CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.

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KW - CD4

KW - Envelope

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KW - Macrophage

KW - Tropism

KW - V1/V2 stem

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Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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