Characterization of two candidate genes, NCoA3 and IRF8, potentially involved in the control of HIV-1 latency.
BACKGROUND
The persistence of latent HIV-1 reservoirs is the principal barrier preventing the eradication of HIV-1 infection in patients by current antiretroviral therapy. It is thus crucial to understand the molecular mechanisms involved in the establishment, maintenance and reactivation of HIV-1 latency. Since chromatin remodeling has been implicated in the transcriptional reactivation of the HIV-1 promoter, we assessed the role of the histone deacetylase inhibitor sodium butyrate (NaB) on two HIV-1 latently infected cell lines (U1 and ACH-2) gene expression.


RESULTS
Analysis of microarrays data led us to select two candidate genes: NCoA3 (Nuclear Receptor Coactivator 3), a nuclear receptor coactivator and IRF8 (Interferon Regulatory Factor 8), an interferon regulatory factor. NCoA3 gene expression is upregulated following NaB treatment of latently infected cells whereas IRF8 gene expression is strongly downregulated in the promonocytic cell line following NaB treatment. Their differential expressions were confirmed at the transcriptional and translational levels. Moreover, NCoA3 gene expression was also upregulated after treatment of U1 and ACH-2 cells with phorbol myristyl acetate (PMA) but not trichostatin A (TSA) and after treatment with NaB of two others HIV-1 latently infected cell lines (OM10.1 and J1.1). IRF8 gene is only expressed in U1 cells and was also downregulated after treatment with PMA or TSA. Functional analyses confirmed that NCoA3 synergizes with Tat to enhance HIV-1 promoter transcription and that IRF8 represses the IRF1-mediated activation through the HIV-1 promoter Interferon-stimulated response element (ISRE).


CONCLUSIONS
These results led us to postulate that NCoA3 could be involved in the transcriptional reactivation of the HIV-1 promoter from latency and that IRF8 may contribute to the maintenance of the latent state in the promonocytic cell line. Implication of these factors in the maintenance or reactivation of the viral latency may provide potential new targets to control HIV-1 replication in latent viral reservoirs.
Munier
Sandie
S
Département des Maladies Infectieuses, Institut Cochin, INSERM U567/CNRS UMR-S 8104/Université Paris 5-René Descartes, 22 rue Méchain, 75014 Paris, France. munier@cochin.inserm.fr
Delcroix-Genête
Delphine
D
Carthagéna
Laëtitia
L
Gumez
Audrey
A
Hazan
Uriel
U
D000123:Acetyltransferases / Q000235:genetics* / Q000502:physiology; D002087:Butyrates / Q000494:pharmacology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D051548:Histone Acetyltransferases; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000502:physiology; D007372:Interferons / Q000494:pharmacology; D019169:Jurkat Cells; D056921:Nuclear Receptor Coactivator 3; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D020218:Response Elements / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D017735:Virus Latency; D014779:Virus Replication; D000099185:Interferon Regulatory Factor-8
D000123:Acetyltransferases; D002087:Butyrates; D051548:Histone Acetyltransferases; D050835:Interferon Regulatory Factors; D007372:Interferons; D056921:Nuclear Receptor Coactivator 3; D012333:RNA, Messenger; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; C538866:NCOA3 protein, human