Nitric oxide modulates HIV-1 replication.
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.
Mannick
J B
JB
Department of Adult Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Joan_Mannick@dfci.harvard.edu
Stamler
J S
JS
Teng
E
E
Simpson
N
N
Lawrence
J
J
Jordan
J
J
Finberg
R W
RW
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004279:DNA, Viral / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008623:Mercaptoethanol; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009603:Nitroso Compounds / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D026403:S-Nitrosothiols; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D015215:Zidovudine / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019380:Anti-HIV Agents; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D014764:Viral Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D015215:Zidovudine; C010005:N-acetylpenicillamine; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D006152:Cyclic GMP