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-1infection remain controversial. We consider here mechanisms that have been suggested, and proposea data-supported model in which CD4+ T-cells undergo apoptosis that is signaled by the binding ofviral gp120 to cellular CD4.Procedures: 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 noninfectiousHIV-1. The cultures were tested for expression of interferon-α, TRAIL, DR5 and apoptosis.Inhibitors of IFNα, TRAIL, DR5 and gp120/CD4 binding were added to the cultures. Ex vivo studieswere performed using peripheral blood mononuclear cells (PBMC) from HIV-1-infected patients totest the validity of our in vitro findings.Findings: Both infectious and noninfectious HIV-1 induced pDC to produce IFNα, which inducedexpression 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 IFNα production, TRAIL and DR5 expression andapoptosis of T helper cells. Studies of HIV-1-infected patients’ PBMC indicated increased plasmaTRAIL production and CD4+ T-cell DR5 expression, which correlated directly with viral load and inverselywith CD4 count.Conclusion: Noninfectious interactions between HIV-1 and CD4 are major contributors to CD4+ T-celldeath via IFNα-induced TRAIL expression and HIV-1-induced DR5 expression on CD4+ T-cells. Sincenoninfectious as well as infectious HIV-1 induces the death cascade resulting in selective apoptosisof CD4+ T-cells, these HIV-1/CD4-dependent binding events would not necessarily be reflected in HIV-1RNA and DNA expression by the CD4+ target T-cells. Because each step of this model leading toapoptosis requires the binding of gp120 to CD4, we suggest that molecules which block this veryearly event in virus/target cell interaction will be effective in preventing or reducing the depletion ofCD4+ T-cells during progression to AIDS. The above mechanisms and the effect of sCD4-IgG are summarizedin our proposed model.