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Title: Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion

Abstract

HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD,more » and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion.« less

Authors:
 [1];  [1];  [2];  [2];  [2];  [2];  [3];  [2];  [4]
  1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA (United States)
  2. Northwestern University Medical School, Chicago, IL (United States)
  3. Department of Pathology, Western General Hospital, University of Edinburgh, Edinburgh (United Kingdom)
  4. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA (United States) and Department of Neurology, Harvard Medical School, Boston, MA (United States). E-mail: dana_gabuzda@dfci.harvard.edu
Publication Date:
OSTI Identifier:
20977003
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 360; Journal Issue: 1; Other Information: DOI: 10.1016/j.virol.2006.09.036; PII: S0042-6822(06)00691-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS; AIDS VIRUS; AUTOPSY; BLOOD; BRAIN; GENES; LYMPH NODES; MACROPHAGES; MUTAGENESIS; NERVOUS SYSTEM DISEASES; NUCLEOTIDES; PATIENTS; PROLINE; RECEPTORS

Citation Formats

Thomas, Elaine R., Dunfee, Rebecca L., Stanton, Jennifer, Bogdan, Derek, Taylor, Joann, Kunstman, Kevin, Bell, Jeanne E., Wolinsky, Steven M., and Gabuzda, Dana. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. United States: N. p., 2007. Web. doi:10.1016/j.virol.2006.09.036.
Thomas, Elaine R., Dunfee, Rebecca L., Stanton, Jennifer, Bogdan, Derek, Taylor, Joann, Kunstman, Kevin, Bell, Jeanne E., Wolinsky, Steven M., & Gabuzda, Dana. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. United States. doi:10.1016/j.virol.2006.09.036.
Thomas, Elaine R., Dunfee, Rebecca L., Stanton, Jennifer, Bogdan, Derek, Taylor, Joann, Kunstman, Kevin, Bell, Jeanne E., Wolinsky, Steven M., and Gabuzda, Dana. Fri . "Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion". United States. doi:10.1016/j.virol.2006.09.036.
@article{osti_20977003,
title = {Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion},
author = {Thomas, Elaine R. and Dunfee, Rebecca L. and Stanton, Jennifer and Bogdan, Derek and Taylor, Joann and Kunstman, Kevin and Bell, Jeanne E. and Wolinsky, Steven M. and Gabuzda, Dana},
abstractNote = {HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion.},
doi = {10.1016/j.virol.2006.09.036},
journal = {Virology},
number = 1,
volume = 360,
place = {United States},
year = {Fri Mar 30 00:00:00 EDT 2007},
month = {Fri Mar 30 00:00:00 EDT 2007}
}