Specific Inhibition of HIV Infection by the Action of Spironolactone in T Cells.
Tat protein, the HIV transactivator, regulates transcription of the HIV genome by the host transcription machinery. Efficient inhibitors of HIV transcription that target Tat or the cellular cofactor NF-κB are well known. However, inhibition of HIV Tat-dependent transcription by targeting the general transcription and DNA repair factor II human (TFIIH) has not been reported. Here, we show that spironolactone (SP), an aldosterone antagonist approved for clinical use, inhibits HIV-1 and HIV-2 infection of permissive T cells by blocking viral Tat-dependent transcription from the long terminal repeat (LTR). We found that treatment of Jurkat and primary CD4+T cells with SP induces degradation of the XPB cellular helicase, a component of the TFIIH complex, without affecting cellular mRNA levels, T cell viability, or T cell proliferation. We further demonstrate that the effect of SP on HIV infection is independent of its aldosterone antagonist function, since the structural analogue, eplerenone, does not induce XPB degradation and does not inhibit HIV infection. Rescue experiments showed that the SP-induced block of HIV infection relies, at least partially, on XPB degradation. In addition, we demonstrate that SP specifically inhibits Tat-dependent transcription, since basal transcription from the LTR is not affected. Our results demonstrate that SP is a specific inhibitor of HIV Tat-dependent transcription in T cells, which additionally suggests that XPB is a cofactor required for HIV infection. Targeting a cellular cofactor of HIV transcription constitutes an alternative strategy to inhibit HIV infection, together with the existing antiretroviral therapy.


OBJECTIVE
Transcription from the HIV promoter is regulated by the combined activities of the host transcription machinery and the viral transactivator Tat protein. Here, we report that the drug spironolactone-an antagonist of aldosterone-blocks viral Tat-dependent transcription, thereby inhibiting both HIV-1 and HIV-2 infection of permissive T cells. This inhibition relies on the degradation of the cellular helicase XPB, a component of the TFIIH transcription factor complex. Consequently, XPB appears to be a novel HIV cofactor. Our discovery of the HIV-inhibitory activity of spironolactone opens the way for the development of novel anti-HIV strategies targeting a cellular cofactor without the limitations of antiretroviral therapy of drug resistance and high cost.
Institut Cochin, INSERM U1016, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Benoît
B
Lacombe
Institut Cochin, INSERM U1016, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Marina
M
Morel
Institut Cochin, INSERM U1016, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Florence
F
Margottin-Goguet
Institut Cochin, INSERM U1016, Paris, France cecilia.ramirez@inserm.fr.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Bertha Cecilia
BC
Ramirez
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D013148:Spironolactone / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014158:Transcription, Genetic / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors
D019380:Anti-HIV Agents; D004268:DNA-Binding Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C072022:XPBC-ERCC-3 protein; D013148:Spironolactone; D004265:DNA Helicases
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