Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease.

Abstract

Mononuclear phagocytes (monocytes, macrophages, and dendritic cells) play major roles in human immunodeficiency virus (HIV) persistence and disease pathogenesis. Macrophage antigen presentation and effector cell functions are impaired by HIV-1 infection. Abnormalities of macrophage effector cell function in bone marrow, lung, and brain likely result as a direct consequence of cellular activation and HIV replication. To further elucidate the extent of macrophage dysfunction in HIV-1 disease, a critical activation-specific regulatory molecule, nitric oxide (NO.), which may contribute to diverse pathology, was studied. Little, if any, NO. is produced by uninfected human monocytes. In contrast, infection with HIV-1 increases NO. production to modest, but significant levels (2-5 microM). Monocyte activation (with lipopolysaccharide, tumor necrosis factor alpha, or through interactions with astroglial cells) further enhances NO. production in HIV-infected cells, whereas its levels are diminished by interleukin 4. These results suggest a possible role for NO. in HIV-associated pathology where virus-infected macrophages are found. In support of this hypothesis, RNA encoding the inducible NO synthase (iNOS) was detected in postmortem brain tissue from one pediatric AIDS patient with advanced HIV encephalitis. Corresponding iNOS mRNA was not detected in brain tissue from five AIDS patients who died with less significant brain disease. These results demonstrate that HIV-1 can influence the expression of NOS in both cultured human monocytes and brain tissue. This newly described feature of HIV-macrophage interactions suggests previously unappreciated mechanisms of tissue pathology that result from productive viral replication.

Reactive oxygen species and nitric oxide in viral diseases

“…Finally, HIV infection (63) and HIV gp120 (64) were shown to enhance the production of NO. in human monocytes and exert neurotoxic effects via NO.…”

Co-Infection with HIV and Mycobacterium tuberculosis: immunologic interactions, disease progression, and survival

“…These factors are cytokines triggered during the immune response to the co-infection, reactive oxygen radicals, and cell-cell contact via the engagement of specific surface receptors. These factors trigger HIV replication or cell to cell transmission of HIV (Ho et al 1995b, Lipton & Gendelman 1995, Bukrinsky et al 1995.…”

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

“…TNF-␣, along with other cytokines, such as IL-1, stimulates gliosis (i.e., increases microglia and astrocytes) [33][34][35]. In addition, TNF-␣ can alter neuronal function, is toxic to oligodendrocytes in vitro [36,37], and stimulates mononuclear phagocytes and astrocytes to produce other potential neurotoxins such as nitric oxide, quinolinic acid, and HIV [19,33,38]. Therefore, TNF-␣ may have a pivotal role, either directly or indirectly influencing the pathogenesis of HIV encephalitis.…”

“…These putative toxins include quinolinic acid, neopterin, arachidonic acid metabolites, Ntox, and others [14][15][16][17][18][19][20][21][22]. Both quinolinic acid and gp120 interact with the NMDA receptor to produce neurotoxicity [14,23,24], and nitric oxide is reported to be synergistic with gp120 in producing neurotoxicity [18].…”

“…TNF-␣, IL-1, and IL-6 are produced by mononuclear phagocytes and astrocytes, whereas IFN-␥ is primarily produced by TH1 type CD4 ϩ T cells, CD8 ϩ T cells, and natural killer (NK) cells [33,38]. In general, these cytokines stimulate cells, including mononuclear phagocytes and astrocytes, to produce other cytokines and other substances, such as eicosanoids, and in certain instances nitric oxide, neopterin, quinolinic acid, and superoxide, which are important to inflammation, neurotoxicity, and tissue destruction [14][15][16][17][18][19]38]. TNF-␣, IL-1, and IL-6 potentiate HIV replication.…”