Two chemokine (chemoattractant cytokines) fJ peptides, macrophage inflammatory proteins la and lip

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.

Quinolinic acid (Quin) is thought to underlie cognitive and motor dysfunctions for a variety of neurological disorders. Specifically, in human immunodeficiency virus (HIV)-associated dementia, Quin levels correlate with the degree of neurological dysfunction observed in affected individuals. Since recent data fiom our laboratories suggest that both HIV-1 infection and activation of brain macrophages are required for the development of neurotoxicity we examined Quin production during virus infection and immune activation. HIV-1 infection of monocytes induced low levels of Quin while lipopolysaccharide (LPS) or interferon-gamma (IFN-y) activation of the virus-infected cells elicited 10-fold higher levels. The combined effects of LPS and IFN-y for Quin production in HIV-infected monocytes was identical to each factor added alone. Little or no Quin was detected in unstimulated uninfected monocytes. LPS or IFN-I/ activation of uninfected monocytes produced substantially higher levels of Quin than found in similarly stimulated HIV-1-infected monocytes. These results were at variance to the production oftumor necrosis factor-alpha (TNFa). Here, a 2-to 5-fold increase in TNF-a levels were observed in culture fluids of US-activated HIV-infected cells when compared to similarly stimulated uninfected monocytes. The effect of LPS-induced Quin production by M Vinfected monocytes was not altered by primary human astrocytes. These data suggest that Quin levels seen in HIV dementia are a reflection of macrophage/ microglial activation seen during advanced clinical disease. These findings could help explain, in part, why few HIV-1-infected brain macrophages can give rise to significant neurological impairments.

HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-alpha. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus-infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-beta independent. Although astrocytes constitutively produced latent TGF-beta 2, HIV-1-infected monocytes neither affected TGF-beta 2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-beta 1 or rTGF-beta 2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-alpha. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus-infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.

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