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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Herbeuval
Jean-Philippe
JP
Experimental Immunology Branch, Centers for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Shearer
Gene M
GM
D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000628:therapy; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007370:Interferon Type I / Q000276:immunology / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000276:immunology / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000627:therapeutic use; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors*; D019562:Viral Load
D051017:Apoptosis Regulatory Proteins; D015699:HIV Envelope Protein gp120; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins