The lung is a major target for opportunistic infections in human immunodeficiency virus (HIV)-seropositive patients and these infections cause significant morbidity and mortality. HIV and cytomegalovirus (CMV) can be detected in lung tissues in vivo and simultaneous infection of individual cells with HIV and CMV occur in lung, brain, retina and placental tissues. We and others have described in vitro bidirectional interactions between HIV and CMV whereby each enhances the replication of the other. Moreover, both HIV and CMV cause substantial immunosuppression that is mediated, in part, by the proinflammatory cytokines. A fundamental concept concerning cytokine-mediated disease has emerged: the relative amounts of the proinflammatory cytokines (eg, interleukin-1 [IL-1] and tumor necrosis factor [TNF]), their antagonists (eg, IL-1 receptor antagonist [IL-1Ra] and soluble TNF receptors [sTNFR]), and the relevant chemokines that are produced during infection or inflammation, influence the pathogenesis, resolution or progression of disease. Little is known about cytokine antagonist or chemokine production in the lung or the influence of CMV coinfection on these factors. Our major hypothesis is that CMV infection of lung tissue and the balance between proinflammatory cytokines, naturally-occurring cytokine antagonists and chemokines determine the amount of HIV replication in the lung and the degree of alveolar macrophage (AM) and CD8 cytotoxic T lymphocyte (CTL) dysfunction. We will test this hypothesis using AM obtained from patients at all stages of HIV-related disease, some of whom will have CMV infection (either latent or active). We will also coinfect AM from HIV-seronegative donors in vitro with HIV and CMV. We will measure the levels of proinflammatory cytokines, cytokine antagonists, and chemokines (MIP-1alpha, MIP-1Beta, and RANTES); the amount of HIV and CMV in lung tissue as compared to plasma and peripheral blood; the changes in proliferative response of AM to mitogens and antigens; and alterations in lung CD8 CTL function. We will attempt to influence these changes using cytokine antagonists and antibodies to the relevant chemokines.
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