Human immunodeficiency virus-1-infected macrophages induce inducible nitric oxide synthase and nitric oxide (NO) production in astrocytes: AstrocyticNO as a possible mediator of neural damage in acquired immunodeficiency syndrome

Nitric oxide (NO) plays an important role in normal neural cell function. D ysregulated or overexpression of NO contributes to neurologic damage associ ated with various pathologies, including human immunodeficiency virus (HIV) -associated neurological disease. Previous studies suggest that HIV-infecte d monocyte-derived macrophages (MDM) produce low levels of MO in vitro and that inducible nitric oxide synthase (iNOS) is expressed in the brain of pa tients with neurologic disease. However, the levels of NO could not account for the degree of neural toxicity observed. In this study, we found that i nduction of iNOS with concomitant production of NO occurred in primary huma n astrocytes, but not in MDM, when astrocytes were cocultured with HIV-1-in fected 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 expre ssion (interferon-gamma. interleukin-1 beta. and tumor necrosis factor-alph a) were not detected. In addition, the recombinant HIV-1 envelope protein g p41, but not rgp120. induced iNOS in cocultures of uninfected MDM and astro cytes. This suggests that astrocytes may be an important source of NO produ ction 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 diseas e may ensue from prolonged, high level production of NO. This is a US gover nment work. There are no restrictions on its use.