Enhanced Replication of Simian Immunodeficiency Virus Adjacent to Catecholaminergic Varicosities in Primate Lymph Nodes

Abstract

Clinical and in vitro studies have shown that activity of the autonomic nervous system (ANS) can stimulate lentivirus replication. To define the potential anatomical basis for this effect, we analyzed the spatial relationship between catecholaminergic neural fibers and sites of simian immunodeficiency virus (SIV) replication in lymph nodes from rhesus macaques experimentally infected with SIVmac251. Viral replication was mapped by in situ hybridization for SIV env, gag, and nef RNA, and catecholaminergic varicosities from the ANS were mapped by sucrose phosphate glyoxylic acid chemofluorescence. Spatial statistical analyses showed that the likelihood of active SIV replication increased by 3.9-fold in the vicinity of catecholaminergic varicosities (P < 0.0001). The densities of both ANS innervation and SIV replication differed across cortical, paracortical, and medullary regions of the lymph node, but analyses of each region separately continued to show increased replication of SIV adjacent to catecholaminergic varicosities. Ancillary analyses ruled out the possibility that SIV-induced alterations in lymph node architecture might create a spurious spatial association. These data support human clinical studies and in vitro molecular analyses showing that catecholamine neurotransmitters from the ANS can increase lentiviral replication by identifying a specific anatomic context for interactions between ANS neural fibers and replication of SIV in lymphoid tissue.

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

“…Lymph nodes for the current study were selected from the pool of 40 fresh frozen lymph nodes. SIV replication within lymph node tissue was confirmed by in situ hybridization using probes to detect SIV env, gag and nef mRNA as previously described (Sloan, et al, 2006;Canto-Nogues, et al, 2001). All procedures were carried out under protocols approved by the Institutional Animal Use and Care and University Institutional Review Boards at the University of California, Davis and Los Angeles campuses.…”

“…Animals came from a larger study comprising 36 male rhesus macaques aged 7-10 years, that were individually housed for the duration of the study. At week 0, twenty-four animals were experimentally infected with SIV (10 2.66 TCID 50 SIV mac251 ), and all became infected as documented by RT-PCR detection of plasma viral genomes (Sloan, et al, 2006). At week 37, four axillary lymph nodes were biopsied from each of 20 macaques, two of which were fresh frozen and the remaining two of which were fixed in OCT.…”

“…Catecholamine signaling has also been found to promote replication of Human Immunodeficiency Virus Type 1 (HIV-1) and the closely related Simian Immunodeficiency Virus (SIV) (Cole, et al, 1998;Cole, et al, 1999;Sloan, et al, 2006). Recent work has shown that sympathetic innervation of peripheral lymphoid organs is dynamic, with altered patterns of innervation observed during aging (Bellinger, et al, 2005), inflammation (Kelley, et al, 2003) and viral infection (Sloan, et al, 2006). Recently, we showed that experimental infection of primates with SIV led to a significant reduction in the density of sympathetic innervation in lymph nodes of rhesus macaques (Sloan, et al, 2006).…”

“…Following activation, catecholamine neurotransmitters are released from varicosities along the length of the nerve fiber and bind adrenergic receptors on immune cells, thereby modulating immune function (Sanders, et al, 2001;Sanders, 2006). Catecholamine signaling has also been found to promote replication of Human Immunodeficiency Virus Type 1 (HIV-1) and the closely related Simian Immunodeficiency Virus (SIV) (Cole, et al, 1998;Cole, et al, 1999;Sloan, et al, 2006). Recent work has shown that sympathetic innervation of peripheral lymphoid organs is dynamic, with altered patterns of innervation observed during aging (Bellinger, et al, 2005), inflammation (Kelley, et al, 2003) and viral infection (Sloan, et al, 2006).…”

“…Recent work has shown that sympathetic innervation of peripheral lymphoid organs is dynamic, with altered patterns of innervation observed during aging (Bellinger, et al, 2005), inflammation (Kelley, et al, 2003) and viral infection (Sloan, et al, 2006). Recently, we showed that experimental infection of primates with SIV led to a significant reduction in the density of sympathetic innervation in lymph nodes of rhesus macaques (Sloan, et al, 2006). Loss of lymphoid innervation has also been observed in the gastrointestinal tract of individuals infected with HIV-1 (Batman, et al, 1991) and the spleen of mice infected with the LM-BP5 mixture of retroviruses (Kelley, et al, 2003).…”