β-Adrenoreceptors Reactivate Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication via PKA-Dependent Control of Viral RTA

Abstract

Reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication is mediated by the viral RTA transcription factor, but little is known about the physiological processes controlling its expression or activity. Links between autonomic nervous system activity and AIDS-associated Kaposi's sarcoma led us to examine the potential influence of catecholamine neurotransmitters. Physiological concentrations of epinephrine and norepinephrine efficiently reactivated lytic replication of KSHV in latently infected primary effusion lymphoma cells via ␤-adrenergic activation of the cellular cyclic AMP/protein kinase A (PKA) signaling pathway. Effects were blocked by PKA antagonists and mimicked by pharmacological and physiological PKA activators (prostaglandin E 2 and histamine) or overexpression of the PKA catalytic subunit. PKA up-regulated RTA gene expression, enhanced activity of the RTA promoter, and posttranslationally enhanced RTA's transactivating capacity for its own promoter and heterologous lytic promoters (e.g., the viral PAN gene). Mutation of predicted phosphorylation targets at RTA serines 525 and 526 inhibited PKA-mediated enhancement of RTA trans-activating capacity. Given the high catecholamine levels at sites of KSHV latency such as the vasculature and lymphoid organs, these data suggest that ␤-adrenergic control of RTA might constitute a significant physiological regulator of KSHV lytic replication. These findings also suggest novel therapeutic strategies for controlling the activity of this oncogenic gammaherpesvirus in vivo.

Detection of polyomaviruses and herpesviruses in human adrenal tumors

“…Herpesviruses have also been shown to reactivate in response to stress and adrenergic stimuli (Bloom et al, 1997;Chang et al, 2005). For example, physiological concentrations of catecholamines have been demonstrated to induce lytic replication of HHV8 in latently infected lymphoid cells via badrenergic activation of cellular protein kinase A signaling pathway (Chang et al, 2005). These observations are in agreement with our findings of HHV8 DNA in a case of normal adrenal cortex adjacent to a pheochromocytoma and in two adrenocortical tumors, which were also positive for other herpesviruses.…”

“…However, glucocorticoids and/or other adrenal steroid hormones could indirectly activate viral replication through induction of expression of other transcription factors and coactivators that bind viralenhancer/promoter sequences and mediate glucocorticoid response. Herpesviruses have also been shown to reactivate in response to stress and adrenergic stimuli (Bloom et al, 1997;Chang et al, 2005). For example, physiological concentrations of catecholamines have been demonstrated to induce lytic replication of HHV8 in latently infected lymphoid cells via badrenergic activation of cellular protein kinase A signaling pathway (Chang et al, 2005).…”

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

“…CREB1 has been implicated in regulating viral gene expression of a number of viruses, including hepatitis B virus (HBV) (29), herpes simplex virus 1 (HSV-1) (30), human cytomegalovirus (HCMV) (31), and human T-cell leukemia virus (HTLV) (32,33). A previous study showed that activation of the cAMP-dependent protein kinase A (cAMP/PKA) pathway, the classic CREB1 upstream pathway, is sufficient to reactivate KSHV from latency (34). However, it has been reported that KSHV infection of DMVEC is nonproductive, with minimal lytic activity (19), despite CREB1 activation via the cAMP/PKA pathway (35).…”

SIV infection decreases sympathetic innervation of primate lymph nodes: The role of neurotrophins

“…This hypothesized link between innate antiviral responses and sympathetic denervation is particularly intriguing given recent indications that sympathetic neurotransmitters can inhibit innate antiviral responses (Collado-Hidalgo, et al, 2006). From this perspective, the localized sympathetic denervation observed here may serve to functionally de-repress Type I interferons (Collado-Hidalgo, et al, 2006) and withdraw catcholaminergic support for viral replication (Prosch, et al, 2000;Bloom, et al, 1994;Leib, et al, 1991;Willey, et al, 1984;Chang, et al, 2005;Turgeman and Aboud, 1998;Cole, et al, 1998;Cole, et al, 1999;Cole, et al, 2001;Sloan, et al, 2006). If true, this hypothesis implies that the dynamic denervation of lymphoid organs in response to viral infection may constitute a neurobiological component of the broader innate immune response to infection.…”