We have recently developed an in vitro system in which normal PBMC are stimulated with soluble antigen, exposed to infectious HIV, and cultured for an additional 2-3 weeks with monitoring of their responsiveness to further immunologic stimuli as well as their production of HIV. This system exhibits many of the features of acquired immunodeficiency syndrome (AIDS), in that a single exposure of PBMC to the soluble antigen tetanus toxoid amplified the susceptibility of PBMC to productive HIV infection by a factor of 10-100, and exposure of antigen-stimulated PBMC to low levels of HIV can inhibit the responsiveness of these cells to further immunologic stimuli. The goal of this proposal is to define the cellular and immunologic mechanisms responsible for these phenomena. First, we will define the factors that determine the magnitude of such antigen- induced amplification of HIV replication, including the time interval between exposure to antigen and exposure to HIV, the dose of HIV, and the dose of antigen. We will then investigate the immunological basis for this amplification by determining a) the identity of the cell in which increased HIV replication occurs after antigenic stimulation (i.e., CD4+ lymphocyte or macrophage, or both), b) whether the responsiveness of these cell populations to antigenic stimulation, as reflected in the production of cytokines and soluble receptors for interleukin 2, correlates with the magnitude of antigen-induced amplification of HIV replication, and c) whether cyclosporin A can inhibit antigen- induced amplification of HIV infection. Next, by analyzing the responses of PBMC that can proliferate in response to 2 or more antigens, we will determine whether antigen-activated CD4+ subpopulations are preferentially infected by HIV, compared to resting populations of specific for other antigens. Finally, we will address the mechanism of HIV-induced inhibition of antigen- and mitogen-induced lymphoproliferative responses, determining a) if it is also amplified by prior antigen-induced activation, as indicated by some preliminary data; and b) whether this effect requires live (infectious) HIV, and, if so, whether a low level productive infection or a reactivated latent infection is involved. These studies will provide insight into the mechanisms that determine susceptibility of human PBMC to infection with HIV and lead to the immunosuppressive effects of such infection, and will provide basic data that may be useful in the development of approaches to limit replication of HIV in infected hosts.
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