MYCOBACTERIUM-AVIUM COMPLEX AUGMENTS MACROPHAGE HIV-1 PRODUCTION AND INCREASES CCR5 EXPRESSION

Infection with HIV-1 results in pronounced immune suppression and susc eptibility to opportunistic infections (OI). Reciprocally, OI augment HIV-1 replication. As we have shown for Mycobacterium avium complex (M AC) and Pneumocystis carinii, macrophages infected with opportunistic pathogens and within lymphoid tissues containing OI, exhibit striking levels of viral replication. To explore potential underlying mechanism s for increased HIV-1 replication associated with coinfection, blood m onocytes were exposed to MAC antigens (MAg) or viable MAC and their le vels of tumor necrosis factor alpha (TNF alpha) and HIV-1 coreceptors monitored. MAC enhanced TNF alpha production in vitro, consistent with its expression in coinfected lymph nodes. Using a polyclonal antibody to the CCR5 coreceptor that mediates viral entry of macrophage tropic HIV-1, a subset of unstimulated monocytes was shown to be CCR5-positi ve by fluorescence-activated cell sorter analysis. After stimulation w ith MAg or infection with MAC, CCR5 expression was increased at both t he mRNA level and on the cell surface. Up-regulation of CCR5 by MAC wa s not paralleled by an increase in the T cell tropic coreceptor, CXCR4 . Increases in NF-kappa B, TNF alpha, and CCR5 were consistent with th e enhanced production of HIV-1 in MAg-treated adherent macrophage cult ures as measured by HIV-1 p24 levels. Increased CCR5 was also detected in coinfected lymph nodes as compared with tissues with only HIV-1. T he increased production of TNF alpha, together with elevated expressio n of CCR5, provide potential mechanisms for enhanced infection and rep lication of HIV-1 by macrophages in OI infected cells and tissues. Con sequently, treating OI may inhibit not only the OI-induced pathology, but also limit the viral burden.