Human Immunodeficiency Virus-1–Infected Macrophages Induce Inducible Nitric Oxide Synthase and Nitric Oxide (NO) Production in Astrocytes: Astrocytic NO as a Possible Mediator of Neural Damage in Acquired Immunodeficiency Syndrome

Abstract

Nitric oxide (NO) plays an important role in normal neural cell function. Dysregulated or overexpression of NO contributes to neurologic damage associated with various pathologies, including human immunodeficiency virus (HIV)-associated neurological disease. Previous studies suggest that HIV-infected monocyte-derived macrophages (MDM) produce low levels of NO in vitro and that inducible nitric oxide synthase (iNOS) is expressed in the brain of patients with neurologic disease. However, the levels of NO could not account for the degree of neural toxicity observed. In this study, we found that induction of iNOS with concomitant production of NO occurred in primary human astrocytes, but not in MDM, when astrocytes were cocultured with HIV-1–infected MDM. This coincided with decreased HIV replication in infected MDM. Supernatants from cocultures of infected MDM and astrocytes also stimulated iNOS/NO expression in astrocytes, but cytokines known to induce iNOS expression (interferon-γ, interleukin-1β, and tumor necrosis factor-) were not detected. In addition, the recombinant HIV-1 envelope protein gp41, but not rgp120, induced iNOS in cocultures of uninfected MDM and astrocytes. This suggests that astrocytes may be an important source of NO production due to dysregulated iNOS expression and may constitute one arm of the host response resulting in suppression of HIV-1 replication in the brain. It also leads us to speculate that neurologic damage observed in HIV disease may ensue from prolonged, high level production of NO.

Nitric oxide and redox mechanisms in the immune response

“…There is a significant mismatch between these promoters that is likely to account for the notable differences in the regulation of gene induction between mice and humans. In rodents and humans, NOS2 mRNA expression is not restricted to macrophagic cells, and iNOS can be found in a number of cell types, including epithelial cells [154,155], astrocytes [156], endothelial cells [157,158], as well as other cell types [159]. Again, multiple differences in the induction of human NOS2 compared with mouse NOS2 are observed in these adjunct immune cells.…”

Role of free radicals in viral pathogenesis and mutation

“…An envelope glycoprotein of HIV, gp41, triggers iNOS expression in human astrocytes and murine cortical brain cells in culture [52,53]. Thus, NO produced by iNOS may contribute directly to the pathogenesis of HIV-associated dementia and cardiomyopathy as well [36,[52][53][54][55]. Similarly, the human paramyxovirus respiratory syncytial virus directly upregulates iNOS in human type 2 alveolar epithelial cells (A549 cells) through a pathway independent of proinflammatory cytokines [56].…”

The role of the proteasome–ubiquitin pathway in regulation of the IFN-γ mediated anti-VSV response in neurons

“…IFN-γ upregulates NOS-1 expression posttranscriptionally and increases NO production, which is essential in the clearance of VSV infection by neurons (Bi and Reiss, 1995;Komatsu, et al, 1996;Chesler et al, 2004). VSV is not unique; other neurotropic viruses whose replication is inhibited by NO include CMV (Cosugi, et al, 2002), HIV (Hori et al, 1999), HSV-1 (Kodukula, et al, 1999), MHV (Lane, et al, 1997), Poliovirus (Komatsu, et al, 1996), and Reovirus (Goody, et al, 2005). But how this antiviral process is regulated largely remains unknown.…”