Differential effect of tumor necrosis factor-alpha and herpes simplex virus type 1 on the Tat-targeted inhibition of human immunodeficiency virus type 1 replication.
In this study, we have examined whether the Tat antagonist can inhibit human immunodeficiency virus type 1 (HIV-1) replication in the presence of cofactors that can activate transcription of HIV-1 provirus by an NF-kappa B-mediated mechanism, such as tumor necrosis factor-alpha (TNF-alpha) or herpes simplex virus type 1 (HSV-1) infection. As a prototype, we have chosen a low-molecular-weight Tat inhibitor, Ro5-3335, and analyzed its effect on HIV-1 replication in the presence of TNF-alpha and HSV-1 infection in acutely infected peripheral blood lymphocytes (PBLs) and T cells. Ro5-3335 inhibited HIV-1 replication both in CEM-174 cells and in PBLs, but the magnitude of the inhibition was inversely related to viral inoculum and the inhibition was only temporary; viral replication resumed at later times postinfection in spite of the continuous presence of the drug. In contrast, Ro5-3335 suppressed TNF-alpha-induced activation of HIV-1 replication in chronically infected T cells and monocytes that both expressed only low levels of HIV-1 constitutively, while its effect in high-expressing OM-10.1 cells was negligible in the presence of TNF-alpha. The inhibition of HIV-1 replication by Ro5-3335 was specific for the Tat-mediated effect and this drug was not able to inhibit the TNF-alpha-induced expression of the tat-defective HIV-1 provirus. In contrast to TNF-alpha, HSV-1-stimulated HIV-1 expression in the ACH-2 cells was effectively inhibited in the presence of Ro5-3335. These results demonstrate that Tat plays an essential role in HSV-1-mediated activation of HIV-1 provirus, while the TNF-alpha complementation of Tat shows cell-type specificity. These observations suggest that inhibition of the Tat function alone may not be sufficient for an effective anti-HIV-1 inhibition.
Popik
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Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Pitha
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D000998:Antiviral Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D015756:Genes, tat; D015497:HIV-1 / Q000254:growth & development*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000382:microbiology; D011758:Pyrroles / Q000494:pharmacology*; D012367:RNA, Viral / Q000378:metabolism; D012191:Retroviridae Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D001570:Benzodiazepinones; D015696:Gene Products, tat; D011758:Pyrroles; D012367:RNA, Viral; D012191:Retroviridae Proteins; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; C072173:Ro 5-3335