Retinoic acid and liver X receptor agonist synergistically inhibit HIV infection in CD4+ T cells by up-regulating ABCA1-mediated cholesterol efflux.
BACKGROUND
Retinoic acids regulate the reverse cholesterol transport by inducing the ATP binding cassette transporter A1 (ABCA1) dependent cholesterol efflux in macrophages, neuronal as well as intestine cells. In the present study, we aim to test the effect of all trans retinoic acid (ATRA) on ABCA1 expression in human CD4+ T cells and the involvement of cholesterol in ATRA mediated anti-HIV effect.


RESULTS
Treatment with ATRA dramatically up-regulated ABCA1 expression in CD4+ T cells in a time and dose dependent manner. The expression of ABCA1 paralleled with increased ABCA1-dependent cholesterol efflux. This induction was dependent on T cell receptor (TCR) signaling and ATRA failed to induce ABCA1 expression in resting T cells. Moreover, ATRA and liver X receptor (LXR) agonist-TO-901317 together had synergistic effect on ABCA1 expression as well as cholesterol efflux. Increased ABCA1 expression was associated with lower cellular cholesterol staining. Cells treated with either ATRA or TO-901317 were less vulnerable to HIV-1 infection. Combination of retinoic acid and TO-901317 further inhibited HIV-1 entry and their inhibitory effects could be reversed by cholesterol replenishment.


METHODS
ABCA1 RNA and protein were determined by real-time PCR and immuno blot methods in cells treated with ATRA. Cholesterol efflux rate was measured in cells treated with ATRA and TO-901317.


CONCLUSIONS
ATRA up-regulates ABCA1 expression and cholesterol efflux in CD4+ T cells and combination of ATRA and liver X receptor (LXR) agonist further enhanced these effects. Increased cholesterol efflux contributed to reduced HIV-1 entry, suggesting that anti-HIV effect of ATRA is mediated through ABCA1.
Laboratory of Molecular Cell Biology, SAIC-Frederick, Inc, Frederick National Laboratory, Frederick, MD 21702, USA.
Hong
H
Jiang
Yunden
Y
Badralmaa
Jun
J
Yang
Richard
R
Lempicki
Allison
A
Hazen
Ven
V
Natarajan
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D002784:Cholesterol / Q000378:metabolism*; D004357:Drug Synergism; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000627:therapeutic use; D019169:Jurkat Cells; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011948:Receptors, Antigen, T-Cell; D013449:Sulfonamides; D014212:Tretinoin; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides