Adrenergic inhibition of innate anti-viral response: PKA blockade of Type I interferon gene transcription mediates catecholamine support for HIV-1 replication

Stress-induced remodeling of lymphoid innervation

“…To assess the net impact of these two dynamics, we assayed the expression of interferon response genes that mediate IFN induction of the cellular "antiviral state" (e.g., IFI27) and found a substantial net suppression (> 50%). SNS suppression of innate antiviral response is consistent with previous in vitro analyses of beta-adrenergic regulation of IFN transcription (Collado-Hidalgo, Sung et al 2006) and in vivo analyses of stress effects on systemic Type I interferon activity (Jensen and Rasmussen 1963;Chang and Rasmussen 1965). Moreover, quantitative mediational analyses of the SIV-infected lymph node data suggest that SNS inhibition of Type I interferon response could potentially account for more than 90% of the total relationship between sympathetic innervation density and SIV replication density.…”

“…NE signals leukocytes via cellular β-adrenergic receptors, which activate the cAMP/PKA signaling cascade to alter antigen presentation, cellular activation, cytokine production, cell trafficking, and effector activities such as cellular cytotoxicity and antibody production (Kammer 1988;Ottaway and Husband 1994;Madden, Sanders et al 1995;Carlson, Fox et al 1997;Panina-Bordignon, Mazzeo et al 1997;Sanders and Straub 2002;SaintMezard, Chavagnac et al 2003). Effects on cytokine response are especially pronounced, with many studies suggesting that sympathetic activation can inhibit the expression of proinflammatory cytokines (Sanders and Kavelaars 2007), suppresses Th1 cytokines in favor of a Th2 profile (Panina-Bordignon, Mazzeo et al 1997;Cole, Korin et al 1998;Kohm and Sanders 1999;Maestroni and Mazzola 2003;Sanders and Kavelaars 2007), and inhibit the expression of Type I interferons (Collado-Hidalgo, Sung et al 2006). The functional significance of these interactions is underscored by the fact that pharmacologic blockade of SNS activity can alter in vivo immune responses to model antigens and pathogen challenges (Madden, Moynihan et al 1994;Kohm and Sanders 1999).…”

“…In the course of our studies on stress regulation of HIV-1 pathogenesis (Cole, Kemeny et al 1996;Cole, Kemeny et al 1997;Cole, Korin et al 1998;Cole, Jamieson et al 1999;Cole, Naliboff et al 2001;Cole, Kemeny et al 2003;Collado-Hidalgo, Sung et al 2006), we recently examined the sympathetic innervation of lymphoid tissues in adult male rhesus macaques that were experimentally infected with the Simian Immunodeficiency Virus (SIV) Sloan, Tarara et al 2006;Sloan, Capitanio et al 2007a;Sloan, Capitanio et al 2007b;Sloan, Cox et al 2007). HIV-1 and SIV are closely related lymphotropic retroviruses that replicate primarily in activated CD4+ T lymphocytes and macrophages within secondary lymphoid organs.…”

“…HIV-1 and SIV are closely related lymphotropic retroviruses that replicate primarily in activated CD4+ T lymphocytes and macrophages within secondary lymphoid organs. Given previous in vitro evidence that NE can accelerate HIV-1 replication by up-regulating viral co-receptors (Cole, Jamieson et al 1999;Cole, Naliboff et al 2001), inducing viral gene transcription (Cole, Korin et al 1998;Cole, Naliboff et al 2001), and inhibiting antiviral cytokine responses (Cole, Korin et al 1998;Collado-Hidalgo, Sung et al 2006), we sought to determine whether SNS neural fibers might be plausible influences on viral replication within lymphoid tissue. We biopsied axillary and inguinal lymph nodes from adult male rhesus macaques after 39 weeks of daily social stress (unstable social conditions: 100 minutes of caging with 1-3 different conspecifics each weekday) or an equivalent amount of non-stressful social interaction (stable social conditions: 100 minutes of caging with the same 2 conspecifics each day) (as detailed in (Capitanio, Mendoza et al 1998;Sloan, Capitanio et al 2007b)).…”

“…These dynamics raise the possibility that localized inflammatory signaling might contribute to the dynamic equilibrium of sympathetic innervation. Given evidence that beta-adrenergic signaling can inhibit several pro-inflammatory cytokines (particularly Type I and II interferons) (Panina-Bordignon, Mazzeo et al 1997;Cole, Korin et al 1998;Collado-Hidalgo, Sung et al 2006), it is conceivable that sympathetic activity might indirectly promote lymphoid innervation by suppressing the neural-inhibitory activity of interferons (Kim, Beck et al 2002). Simultaneous assessment of neurotrophin and cytokine signaling are needed to comprehensively define physiologic determinants of sympathetic innervation.…”