CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue

Michael L. Penn, Jean-Charles B. Grivel, Birgit Schramm, Mark A. Goldsmith, Leonid Margolis

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

The human chemokine receptors CCR5 and CXCR4 have emerged as the predominant cofactors, along with CD4, for cellular entry of HIV-1 in vivo whereas the contribution of other chemokine receptors to HIV disease has not been yet determined. CCR5-specific (RS) viruses predominate during primary HIV-1 infection whereas viruses with specificity for CXCR4 (R5/X4 or X4 viruses) often emerge in late stages of HIV disease. The evolution of X4 viruses is associated with a rapid decline in CD4+ T cells, although a causative relationship between viral tropism and CD4+ T cell depletion has not yet been proven. To rigorously test this relationship, we assessed CD4+ T cell depletion in suspensions of human peripheral blood mononuclear cells and in explants of human lymphoid tissue on exposure to paired viruses that are genetically identical (isogenic) except for select envelope determinants specifying reciprocal tropism for CXCR4 or CCR5. In both systems, X4 HIV-1 massively depleted CD4+ lymphocytes whereas matched R5 viruses depleted such cells only mildly despite comparable viral replication kinetics. These findings demonstrate that the coreceptor specificities of HIV-1 are a causal factor in CD4+ T cell depletion ex vivo and strongly support the hypothesis that the evolution of viral envelope leading to usage of CXCR4 in vivo accelerates loss of CD4+ T cells, causing immunodeficiency.

Original languageEnglish
Pages (from-to)663-668
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number2
Publication statusPublished - 19 Jan 1999
Externally publishedYes

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Lymphoid Tissue
HIV-1
Viruses
T-Lymphocytes
Chemokine Receptors
Viral Tropism
HIV
Tropism
HIV Infections
Blood Cells
Suspensions
Lymphocytes

ASJC Scopus subject areas

  • General

Cite this

CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue. / Penn, Michael L.; Grivel, Jean-Charles B.; Schramm, Birgit; Goldsmith, Mark A.; Margolis, Leonid.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 2, 19.01.1999, p. 663-668.

Research output: Contribution to journalArticle

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