Nitric Oxide Modulates HIV-1 Replication

Abstract

Although nitric oxide (NO) production is increased in HIV-1-infected patients, and NO is known to inhibit the replication of several viruses, very little is known about the effects of NO on HIV-1 replication. In the present studies, we find that S-nitrosothiols (RSNOs), a class of NO donor compounds present in the human circulatory system, inhibit HIV-1 replication in acutely infected human peripheral blood mononuclear cells (PBMCs) and have an additive inhibitory effect on HIV-1 replication in combination with 3'-azido-3'-deoxythymidylate (AZT). RSNOs inhibit HIV-1 replication in acutely infected PBMCs at a step in the viral replicative cycle after reverse transcription, but before or during viral protein expression through a cGMP-independent mechanism. In the latently infected U1 cell line, NO donor compounds and intracellular NO production stimulate HIV-1 reactivation. These studies suggest that NO both inhibits HIV-1 replication in acutely infected cells and stimulates HIV-1 reactivation in chronically infected cells. Thus, NO may have a physiologic role in HIV-1 replication, and NO donor compounds, which have been used for decades in the treatment of coronary artery disease with limited toxicity, might be useful in the treatment of HIV-1 disease by inhibiting acute infection, reactivating latent virus, or both.

Regulation of Human Immunodeficiency Virus Type 1 Replication in Human T Lymphocytes by Nitric Oxide

“…In addition, it has been reported that the NO donor, S-nitrosoglutathione (GSNO), decreases viral replication in PBMC (39). The reasons for the discrepancies with our results are unknown, but they may depend on the different NO donors used that varied in the speed and amount of NO released.…”

“…At those concentrations, no effect on cell proliferation or cell survival was observed. In contrast, others have shown that high concentrations of NO (as those supplied by GSNO) inhibit NF-B activation (13,51,58) and HIV-1 replication (39). At those concentrations, NO has been shown to reduce cell proliferation and to cause apoptosis (3,65).…”

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…Antioxidants may therefore silence transcriptional activity (109,110), while pro-oxidants, such as arsenic trioxide, may reactivate the viral reservoir (112). By the same token, both NO donors and endogenously generated NO may stimulate HIV reactivation (113). Relatedly, Kahn et al (114) showed that anticancer conditioning agents (doxorubicin, etoposide, fludarabine phosphate, or vincristine) were able to induce HIV escape from latency and that this was associated with increased apoptosis rates (114).…”

S-nitrosothiols regulate cell-surface pH buffering by airway epithelial cells during the human immune response to rhinovirus

“…This suggests the possibility that cytokine/NOSassociated airway epithelial pH buffering could help prevent spread of HRV in the lower airway; HRV rarely causes true pneumonia in immunocompetent hosts. Of note, NOS activation itself, presumably independently of pH, can inhibit viral replication, both through S-nitrosylation-based inhibition of viral cysteine proteases (31,43) and through impaired hostdefense gene regulation (49). Furthermore, a fall in pH results in 1) augmented protein S-nitrosylation (43) and 2) conversion of nitrite to NO (25), both of which could augment the antiviral effect of NOS products.…”