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

Elaine R. Thomas, Rebecca L. Dunfee, Jennifer Stanton, Derek Bogdan, Joann Taylor, Kevin Kunstman, Jeanne E. Bell, Steven M. Wolinsky, Dana Gabuzda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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, 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.

Original languageEnglish (US)
Pages (from-to)105-119
Number of pages15
JournalVirology
Volume360
Issue number1
DOIs
StatePublished - Mar 30 2007

Funding

We thank J. Sodroski, B. Korber, P. Gorry, J. Moore, P. Ancuta, N. Madani, K. Agopian and J. Wang for helpful discussions and advice, and S. Lee for statistical analysis. We also thank D. Kabat for providing JC53 cells; J. Sodroski for rabbit anti-gp120 sera, PS3 and PS4; J. Robinson for MAbs 17b and 19e; the NIH AIDS Reagent Program for TAK-779, 2D7, b12, 2F5, PS1 and PS2; and J Strizki of Schering-Plough Research Institute for AD101. This work was supported by NIH NS37277. Core facilities were supported by Harvard Medical School Center for AIDS Research (CFAR) and DFCI/Harvard Cancer Center grants. The Edinburgh HIV Brain and Tissue Bank is supported by a grant from MRC.

Keywords

  • Brain
  • CD4
  • Envelope
  • Human immunodeficiency virus type 1 (HIV)
  • Lymph node
  • Neurotropism

ASJC Scopus subject areas

  • Virology

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this