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AIDS Rev. 2006 Jan-Mar;8(1):3-8.

Are blockers of gp120/CD4 interaction effective inhibitors of HIV-1 immunopathogenesis?

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Experimental Immunology Branch, Centers for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.



The immunopathogenic mechanisms that result in the depletion of CD4+ T-cells after HIV-1 infection remain controversial. We consider here mechanisms that have been suggested, and propose a data-supported model in which CD4+ T-cells undergo apoptosis that is signaled by the binding of viral gp120 to cellular CD4.


Blood leucocytes from HIV-1-uninfected donors, including CD4+ and CD8+ T-cells, monocytes, myeloid and plasmacytoid dendritic cells (pDC) were cultured with either infectious or noninfectious HIV-1. The cultures were tested for expression of interferon-alpha, TRAIL, DR5 and apoptosis. Inhibitors of IFNalpha, TRAIL, DR5 and gp120/CD4 binding were added to the cultures. Ex vivo studies were performed using peripheral blood mononuclear cells (PBMC) from HIV-1-infected patients to test the validity of our in vitro findings.


Both infectious and noninfectious HIV-1 induced pDC to produce IFNalpha, which induced expression of TRAIL by CD4+ but not CD8+ T-cells. CD4+ T-cells expressed the TRAIL death receptor 5 (DR5), upon HIV-1 binding to CD4. Antibodies against TRAIL and DR5 partly inhibited apoptosis. However, soluble CD4 (sCD4-IgG) efficiently blocked IFNalpha production, TRAIL and DR5 expression and apoptosis of T helper cells. Studies of HIV-1-infected patients' PBMC indicated increased plasma TRAIL production and CD4+ T-cell DR5 expression, which correlated directly with viral load and inversely with CD4 count.


Noninfectious interactions between HIV-1 and CD4 are major contributors to CD4+ T-cell death via IFNalpha-induced TRAIL expression and HIV-1-induced DR5 expression on CD4+ T-cells. Since noninfectious as well as infectious HIV-1 induces the death cascade resulting in selective apoptosis of CD4+ T-cells, these HIV-1/CD4-dependent binding events would not necessarily be reflected in HIV-1 RNA and DNA expression by the CD4+ target T-cells. Because each step of this model leading to apoptosis requires the binding of gp120 to CD4, we suggest that molecules which block this very early event in virus/target cell interaction will be effective in preventing or reducing the depletion of CD4+ T-cells during progression to AIDS. The above mechanisms and the effect of sCD4-lgG are summarized in our proposed model.

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