Host Cell Gene Expression during Human Immunodeficiency Virus Type 1 Latency and Reactivation and Effects of Targeting Genes That Are Differentially Expressed in Viral Latency

Abstract

The existence of reservoirs of cells latently infected with human immunodeficiency virus (HIV) is a major obstacle to the elimination of HIV infection. We studied the changes in cellular gene expression that accompany the reactivation and completion of the lytic viral cycle in cell lines chronically infected with HIV-1. We found that several genes exhibited altered expression in the chronically infected cells compared to the uninfected parental cells prior to induction into lytic replication. A number of gene classes showed increased expression in the chronically infected cells, notably including genes encoding proteasomes, histone deacetylases, and many transcription factors. Following induction of the lytic replication cycle, we observed ordered, time-dependent changes in the cellular gene expression pattern. Approximately 1,740 genes, many of which fall into 385 known pathways, were differentially expressed (P < 0.001), indicating that completion of the HIV replication cycle is associated with distinct, temporally ordered changes in host cell gene expression. Maximum changes were observed in the early and intermediate phases of the lytic replication cycle. Since the changes in gene expression in chronically infected cells suggested that cells latently infected with HIV have a different gene expression profile than corresponding uninfected cells, we studied the expression profiles of three different chronically infected cell lines to determine whether they showed similar changes in common cellular genes and pathways. Thirty-two genes showed significant differential expression in all cell lines studied compared to their uninfected parental cell lines. Notable among them were cdc42 and lyn, which were downregulated and are required for HIV Nef binding and viral replication. Other genes previously unrelated to HIV latency or pathogenesis were also differentially expressed. To determine the effects of targeting products of the genes that were differentially expressed in latently infected cells, we treated the latently infected cells with a proteasome inhibitor, clastolactacystin-beta-lactone (CLBL), and an Egr1 activator, resveratrol. We found that treatment with CLBL and resveratrol stimulated lytic viral replication, suggesting that treatment of cells with agents that target cellular genes differentially expressed in latently infected cells can stimulate lytic replication. These findings may offer new insights into the interaction of the latently infected host cell and HIV and suggest therapeutic approaches for inhibiting HIV infection and for manipulating cells latently infected with HIV so as to trigger lytic replication.

The early expressed HIV-1 genes regulate DNMT1 expression

“…4). The chemopreventative agent Resveratrol inhibits AP-1 transcriptional activity 60 and depletes the HIV-1 reservoir in infected cells; 61 we show that Resveratrol inhibits HIV-1's ability to induce DNMT1 expression. To our knowledge, this is the first example that Resveratrol can be used to block the induction of DNMT1 which has implications as a chemopreventative agent through the inhibition of inappropriate DNMT1 expression.…”

Rho’ing in and out of cells

“…In a transcriptome study in cell lines latently infected with HIV, Cdc42 expression was found to be downregulated, which perhaps may be involved in cellular maintenance of latency. 111 Overall, although there is considerable evidence that Rho GTPase signaling may be involved in regulating viral gene expression during productive viral replication for different viruses, the potential contribution of Rho GTPase signaling during viral latency is less well documented thus far.…”

High-throughput Screening Uncovers a Compound That Activates Latent HIV-1 and Acts Cooperatively with a Histone Deacetylase (HDAC) Inhibitor

“…It was shown that the latent reservoir was still present in HIV-1 patients after long-term ART and simultaneous VA treatment for neurological and psychiatric disorders (12,13). Other small molecules, such as suberoylanilide hydroxamic acid (SAHA) (14 -16), resveratrol (17), and prostratin (18,19), have been proposed as potential agents for the disruption of HIV latent infection. Prostratin induces the NF-B activation pathway (20,21), which puts into question its use in clinical studies because abnormal NF-B signaling has been related to the pathophysiology of cancer, inflammatory diseases, and neurodegenerative disorders (22)(23)(24)(25).…”