A synthetic retinoid antagonist inhibits the human immunodeficiency virus type 1 promoter.
Retinoids regulate a broad range of biological processes and affect cell growth and differentiation of many cell types, including the immune system. Recently, it was reported that human immunodeficiency virus type 1 (HIV-1) expression in macrophages is enhanced by retinoic acid (RA). Retinoid signals are mediated by the RA receptors (RARs) and retinoid X receptors (RXRs) that bind to specific RA responsive elements (RAREs) in the promoter region of susceptible genes. Here, we report on a RARE in the long terminal repeat (LTR) region that allows activation of the HIV-1 LTR. The RARE is composed of two consensus RARE half-sites (A/GGGTCA) arranged as a palindrome separated by 9 nucleotides and is activated by both RAR/RXR heterodimers and RXR homodimers. We show that the COUP (chicken ovalbumin upstream promoter) orphan receptors also bind to the HIV-1 RARE and repress the retinoid response of the HIV-1 RARE or the HIV-1 LTR. Furthermore, a newly discovered synthetic retinoid is shown to be a potent inhibitor of retinoid-induced activation of the HIV-1 RARE. These observations suggest additional approaches for the inhibition of HIV replication.
Lee
M O
MO
Cancer Center, La Jolla Cancer Research Foundation, CA 92037.
Hobbs
P D
PD
Zhang
X K
XK
Dawson
M I
MI
Pfahl
M
M
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D010047:Ovalbumin