Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

Abstract

A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSV expresses a long noncoding RNA and a set of microRNAs, but viral proteins are not expressed. The mechanism by which latent HSV reactivates is unknown. A key question is, what is the mechanism of reactivation in the absence of tegument proteins that enable gene expression in productive infection? Elsewhere we have reported the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to NGF or delayed reactivation in medium containing NGF and EGF. We also reported that in the ganglionic organ cultures incubated in medium containing antibody to NGF, all viral genes are derepressed at once without requiring de novo protein synthesis within the time frame of a single replicative cycle. Here we report that latent HSV in ganglia immersed in medium containing NGF and EGF is reactivated by (i) broad spectrum as well as specific histone deacetylase 1 or histone deacetylase 4 inhibitors, (ii) activation of p300/CBP, and (iii) either STAT3 carrying the substitution of tyrosine 705 to phenylalanine or an inhibitor of STAT3. Conversely, reactivation of latent HSV was blocked by p300/CBP inhibitor in medium containing antibody to NGF. The results suggest that (i) STAT3 is required for the maintenance of the latent state and interference with its functions leads to reactivation and (ii) p300/CBP is essential for HSV reactivation.latency-associated transcript | nerve growth factor

miR-H28 and miR-H29 expressed late in productive infection are exported and restrict HSV-1 replication and spread in recipient cells

“…Total RNAs were extracted from murine trigeminal ganglia (TG) harboring latent viruses or from infected cells by the mirVana miRNA Isolation Kit (Ambion) or TRIzol reagent (Invitrogen) according to the manufacturer's instructions and earlier reports (32,33). Murine model studies of HSV-1 latent infection and reactivation were performed at the University of Chicago as described elsewhere (32), according to protocols approved by the Institutional Animal Care and Use Committee of the University of Chicago.…”

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

“…In medium containing NGF and EGF, the virus remains silent for ∼18-24 h. Studies on this model revealed that in ganglia maintained in medium containing NGF plus EGF, the virus is maintained in a dynamic equilibrium that is disrupted by inhibitors of HDAC-1 and -4, the PI3K-AKT-mTOR and STAT3 pathways, or proapoptotic drugs (10,11). Reactivation in medium containing anti-NGF antibody is inhibited by the expression of REST or by a p300/CBP inhibitor (11,12). Perhaps more significant for reactivation, in neurons all genes are expressed at once rather than sequentially in a coordinated fashion as is seen in infected cells at the portal of entry.…”

Herpes Simplex Virus and Neurotrophic Factors

“…Indeed, HSV establishes latency in neurons that depend on NGF and incubation with NGF and epidermal growth factor delays HSV reactivation [13][14][15][16][17]. Moreover, blocking of NGF with antibodies or depletion of NGF results in HSV reactivation in vitro, ex vivo and in animal models [17][18][19][20][21][22][23]. An explanation for this could be the trigger of caspase 3-dependent apoptosis following NGF depletion [23][24][25].…”

“…Moreover, blocking of NGF with antibodies or depletion of NGF results in HSV reactivation in vitro, ex vivo and in animal models [17][18][19][20][21][22][23]. An explanation for this could be the trigger of caspase 3-dependent apoptosis following NGF depletion [23][24][25]. However, the molecular mechanisms leading to reactivation seem to differ when apoptosis is triggered in the presence of NGF [26].…”

“…This result together with the fact that viral reactivation due to NGF removal is not strictly dependent on caspase-dependent apoptosis [22] suggests that induction of apoptosis is not the sole trigger of reactivation following NGF removal. Recent work indicates a role for STAT3 and p300/CBP in the control of HSV-1 reactivation since inactivation of STAT3 induces HSV reactivation even in the presence of NGF and EGF [23]. Activation of p300/CBP induced HSV reactivation in mouse trigeminal ganglia while inhibition of this transcriptional coactivator had the opposite effect.…”