Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-I.
To investigate the mechanism by which immune activation augments replication of the human immunodeficiency virus type 1 (HIV-1) in infected T cells, four different classes of T cell mitogens were evaluated for their effects on the HIV-1 long terminal repeat (LTR). Phytohemagglutinin (PHA), a mitogenic lectin; phorbol 12-myristic 13-acetate, a tumor promoter; ionomycin, a calcium ionophore; and tat-1, the trans-activator protein from the human T cell leukemia/lymphoma virus type I (HTLV-I) each stimulated the HIV-1 LTR. Studies of deleted forms of the LTR supported a central role in these responses for the HIV-1 enhancer, which alone was sufficient for mitogen inducibility, but also suggested that other 5' positive and negative regulatory elements contribute to the overall magnitude of the response. Synergistic activation of the HIV-1 LTR (up to several thousandfold) was observed with combinations of these mitogens and the HIV-1--derived tat-III protein. Cyclosporin A, an immunosuppressive agent, inhibited PHA-mediated activation of the HIV-1 LTR but was without effect in the presence of other mitogens. Thus, HIV-1 gene expression and replication appear to be regulated, via the HIV-1 LTR, by the same mitogenic signals that induce T cell activation.
Siekevitz
M
M
Howard Hughes Medical Institute, Duke University School of Medicine, Durham, NC 27710.
Josephs
S F
SF
Dukovich
M
M
Peffer
N
N
Wong-Staal
F
F
Greene
W C
WC
D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology; D017977:Deltaretrovirus / Q000502:physiology*; D005814:Genes, Viral; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D008934:Mitogens / Q000494:pharmacology*; D012191:Retroviridae Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014775:Virus Activation / Q000187:drug effects
D003524:Cyclosporins; D008934:Mitogens; D012191:Retroviridae Proteins; D015534:Trans-Activators; D014157:Transcription Factors