Abstract
Latent infection is a major barrier for cure of HIV-1 infection. HIV-1 is capable of establishing latency when its host cells undergo apoptosis and initiate replication in response to this effect. HIV infection results in increased p53 expression that enhances replication in primary infection. To examine whether p53 reactivates HIV-1 replication from latent infection, we used susceptible U1 cells chronically infected with HIV-1 to study the effects of p53 on reactivation of HIV-1 replication in the monocyte/macrophage cell reservoir. We found that p53 could reactivate HIV-1 replication from latency in U1 cells with upregulation/activation of host transcription factors, NF-κB, NFAT, AP1, SP1 and c-Fos, and through modulation of PI3K/Akt and MAPK Erk/p38 signaling pathways. p53 induced P-TEFb signaling with upregulation of CDK6 and Cyclin T1, and increased phosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II.
Highlights
Human Immunodeficiency Virus type-1 (HIV-1) infection of humans causes progressive destruction of CD4+ T cells, as well as chronic immune activation resulting in immune exhaustion and depletion of uninfected immune cells
We found that p53 could reactivate HIV-1 replication from latency in U1 cells with upregulation/activation of host transcription factors, NF-κB, NFAT, AP1, SP1 and c-Fos, and through modulation of PI3K/Akt and Mitogen-Activated Protein Kinases (MAPKs) Erk/p38 signaling pathways. p53 induced positive transcription elongation factor b (P-TEFb) signaling with upregulation of CDK6 and Cyclin T1, and increased phosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II
We found that p53 upregulated CD4, LEDGE/p74 and Poly (ADP-Ribose) Polymerase 1 (PARP-1) and downregulated COMMD1 in U1 cells. p53 expression resulted in the increased expression of acetyl transferase P300/CBP-Associated Factor (PCAF) and decreased expression of de-acetylation HDAC1/2 and SIRT1, which facilitate access of RNA polymerase II to active chromatin to enhance HIV-1 replication
Summary
Human Immunodeficiency Virus type-1 (HIV-1) infection of humans causes progressive destruction of CD4+ T cells, as well as chronic immune activation resulting in immune exhaustion and depletion of uninfected immune cells. To cure HIV-1 infection, it is essential to consider all possible long-term HIV-1 reservoirs harboring either the latent or active form of the virus. The recruitment of P-TEFb (positive Transcription Elongation Factor b by Brd (Bromodomain containing protein 4) during the elongation stage is important for the full length synthesis of HIV-1 mRNA, which is manipulated by the Tat protein essential for viral replication. Cumulative evidence has shown that virus enhances its replication when host cells initiate the apoptotic program This phenomenon is called an Alternative Replication Program (ARP), a process when the host cell is undergoing apoptosis during viral infection. Using U1 cells, we found that p53 expression was able to activate HIV-1 replication from latent infection via upregulation of several host transcription factors in U1 cells
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