Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression.
Infection with HIV-1 results in pronounced immune suppression and susceptibility to opportunistic infections (OI). Reciprocally, OI augment HIV-1 replication. As we have shown for Mycobacterium avium complex (MAC) and Pneumocystis carinii, macrophages infected with opportunistic pathogens and within lymphoid tissues containing OI, exhibit striking levels of viral replication. To explore potential underlying mechanisms for increased HIV-1 replication associated with coinfection, blood monocytes were exposed to MAC antigens (MAg) or viable MAC and their levels of tumor necrosis factor alpha (TNFalpha) and HIV-1 coreceptors monitored. MAC enhanced TNFalpha 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-positive by fluorescence-activated cell sorter analysis. After stimulation with MAg or infection with MAC, CCR5 expression was increased at both the mRNA level and on the cell surface. Up-regulation of CCR5 by MAC was not paralleled by an increase in the T cell tropic coreceptor, CXCR4. Increases in NF-kappaB, TNFalpha, and CCR5 were consistent with the enhanced production of HIV-1 in MAg-treated adherent macrophage cultures as measured by HIV-1 p24 levels. Increased CCR5 was also detected in coinfected lymph nodes as compared with tissues with only HIV-1. The increased production of TNFalpha, together with elevated expression of CCR5, provide potential mechanisms for enhanced infection and replication of HIV-1 by macrophages in OI-infected cells and tissues. Consequently, treating OI may inhibit not only the OI-induced pathology, but also limit the viral burden.
Oral Infection and Immunity Branch, National Institute of Dental Research, 30 Convent Drive, MSC 4352, MD 20892, USA. smwahl@yoda.nidr.nih.gov
S M
SM
Wahl
T
T
Greenwell-Wild
G
G
Peng
H
H
Hale-Donze
T M
TM
Doherty
D
D
Mizel
J M
JM
Orenstein
D017088:AIDS-Related Opportunistic Infections / Q000821:virology; D002478:Cells, Cultured; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000821:virology*; D008561:Membrane Fusion; D015269:Mycobacterium avium Complex / Q000502:physiology*; D015270:Mycobacterium avium-intracellulare Infection / Q000150:complications / Q000821:virology; D019713:Receptors, CCR5 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation; D014779:Virus Replication / Q000502:physiology*
D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha