Cellular liberation of CD4 in HIV-1 disease

Cynthia L. Bristow. Laboratory of Cellular Physiology and Immunology, The Rockefeller University and Population Council, New York, NY 10021 (USA)

Background: Cell surface expression of specific chemokine receptors and CD4 is necessary, but not sufficient, to confer HIV-1 permissivity. Decreased viral RNA is significantly correlated with decreased  circulating a1PI in HIV-1 seropositive individuals. The relationship between a1PI and HIV disease suggested the potential participation of an additional coreceptor cognate for a1PI. Material and Methods: HIV-1 binding and infectivity were compared with the cell surface density and co-patching of human leukocyte elastase (HLE) and the canonical HIV-1 receptors on U937 permissive and non-permissive clones, peripheral blood cells, and small platelet-like transitory bodies (SPTBalls). Results: The N-terminal fusion domain of HIV-1 gp41 binds human leukocyte elastase (HLE) suggesting a nonenzymatic receptor function for cell surface HLE in the context of HIV-1. HLE is found localized to the cell surface, but not granules in HIV-1 permissive clones, and to granules, but not the cell surface of HIV-1 non-permissive clones. Inducing cell surface HLE expression on HLE null, HIV-1 non-permissive clones permits HIV-1 infectivity. HIV-1 binding and infectivity diminish in proportion to HLE RNA subtraction. Increased HIV-1 infectivity is correlated with increased cell surface density of HLE, but not with CD4, CXCR4, or CCR5. HIV-1 binding and infectivity show dose dependence for the natural HLE ligand a1proteinase inhibitor (a1antitrypsin,a1PI). Chemokines prevent, whereas a1PI promotes co-patching of HLE with the canonical HIV-1 receptors. A sequence of events is initiated by a1PI in which HIV-1 co-receptors are initially disperse, are stimulated to co-patch within 15 minutes of exposure of cells to a1PI, and then pinch off from the plasma membrane on SPTBalls. Densely co-patched receptors are retained on SPTBalls which bind HIV-1 imparting a mechanism for uncoupling infectivity. The increase in CD4+ SPTBalls is highly correlated with the decrease in CD4+ lymphocytes in HIV-1 infected patients explaining, in part, the decreased detection of these cells as HIV disease progresses. Conclusions: Results are consistent with a model in which HLE and a1PI can serve as HIV-1 coreceptor and cofactor, respectively, and potentially participate in the pathophysiology of HIV disease progression. A model is proposed in which the acquired a1PI deficiency attendant to HIV-1 disease produces uncontrolled HLE and the consequential pathologic duality of decreased CD4+ lymphocytes and susceptibility to relevant opportunistic infections.