HOST DEFENSE AGAINST HISTOPLASMA CAPSULATUM IN AIDS

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Acquired immunodeficiency syndrome (AIDS) is an immunoregulatory disorder characterized by the presence of Kaposi's sarcoma or opportunistic infections. CD4+ T cells and mononuclear phagocytes are the target cells for the human immuno- deficiency virus (HIV), the etiologic agent of AIDS. Monocyte/macrophages (M-phi) are the major reservoir of HIV and, therefore, a critical concern for the host is the functional capacity of M# from HIV+ individuals to destroy opportunistic pathogens. Disseminated histoplasmosis is seen with increasing frequency as a complication of AIDS, particularly in areas where Histoplasma capsulatum (Hc) is endemic. AIDS patients with disseminated histoplasmosis have a high rate of relapse even after apparently successful therapy with amphotericin B. Therefore, it is imperative that we gain a better understanding of the interaction of Hc with M-phi from HIV+ patients. The goal of the proposed study is to characterize the intrinsic defects in the function of monocyte/M-phi from patients with HIV infection with respect to their ability to defend against Hc. The specific aims of this proposal are: l) To quantify the capacity of M-phi from HIV-infected patients to bind and to phagocytose Hc yeasts and microconidia compared to M-phi from HIV- individuals; 2) To determine if M-phi from HIV-infected patients provide a more than normal permissive environment for the conversion of Hc microconidia into the pathogenic yeast phase, or permit more rapid multiplication of yeasts than normal M-phi; and 3) To quantify the capacity of M-phi from HIV-infected patients to be activated by colony stimulating factors (CSFs) to inhibit the intracellular multiplication of Hc yeasts compared to M-phi from HIV- individuals. As changes in M-phi function may correlate with disease progression and not merely HIV infection, monocyte/M-phi will be studied from different patient groups, from those who are at risk for HIV infection but who are not infected to patients with AIDS. In addition, studies will be performed on normal M-phi infected with HIV in vitro to determine if HIV infection alone can cause M-phi dysfunction with respect to its interaction with Hc.