Herpes Simplex Virus 2 in Autonomic Ganglia: Evidence for Spontaneous Reactivation

Abstract

Herpes simplex virus 2 (HSV-2) can be transmitted in the presence or absence of lesions, allowing efficient spread among the general population. Recurrent HSV genital lesions are thought to arise from reactivated latent virus in sensory cell bodies of the dorsal root ganglia (DRG). However, HSV-2 has also been found latent in autonomic ganglia. Spontaneous reactivation or a low level of chronic infection could theoretically also occur in these peripheral nervous tissues, contributing to the presence of infectious virus in the periphery and to viral transmission. Use of a recently described, optimized virus with a monomeric mNeonGreen protein fused to viral capsid protein 26 (VP26) permitted detection of reactivating virus in explanted ganglia and cryosections of DRG and the sacral sympathetic ganglia (SSG) from latently infected guinea pigs. Immediate early, early, and late gene expression were quantified by droplet digital reverse transcription-PCR (ddRT-PCR), providing further evidence of viral reactivation not only in the expected DRG but also in the sympathetic SSG. These findings indicate that viral reactivation from autonomic ganglia is a feature of latent viral infection and that these reactivations likely contribute to viral pathogenesis. IMPORTANCE HSV-2 is a ubiquitous important human pathogen that causes recurrent infections for the life of its host. We hypothesized that the autonomic ganglia have important roles in viral reactivation, and this study sought to determine whether this is correct in the clinically relevant guinea pig vaginal infection model. Our findings indicate that sympathetic ganglia are sources of reactivating virus, helping explain how the virus causes lifelong recurrent disease.

Is the ZIKV Congenital Syndrome and Microcephaly Due to Syndemism with Latent Virus Coinfection?

“…In one study, 24% of patients showed systemic symptoms, such as fever, headaches, and malaise [ 133 ]. Typically, 10–14 days post-exposition, alphaherpesvirus latency is established within the cell body’s nucleus of sensory nerves (e.g., cervical, lumbosacral, or autonomic ganglia) [ 141 ].…”

“…Short noncoding RNAs along with long noncoding RNAs (lncRNAs) are LAT transcripts typically involved in the maintenance of latency [ 114 , 142 , 143 ]. Nevertheless, not all infected latency cells express LATs, and some studies support the function of LATs in reactivation or, at least, in establishing a high risk of spontaneous reactivation [ 141 ]. The expression of lytic transcripts in latency is favorable for reactivation events rather than silent states, heightening the susceptibility to triggering factors ( Table 2 ).…”

“…Contrary to past beliefs, the viral reactivation risks of asymptomatic infection are as likely as those that have been clinically evidenced [ 144 ]. Recurrent infections may occur all along the reproductive life span; the female mucosal urogenital tract epithelium is more prone to asymptomatic shedding than men’s genital skin [ 144 ], especially in pregnancy [ 138 , 141 ]. Pregnancy-induced HSV-2 reactivation provides an opportunity for mother-to-fetus silent transmission, possibly associated with congenital HSV-2 infection ( Table 3 ) [ 145 , 146 ].…”

“…The HSV-2 reactivation from superinfection by other sexually transmitted pathogens, such as HIV or HPV, may also unbalance the microbiota in the Female Genital Tract (FGT), favoring bacterial vaginosis (BV) and thus enhancing the pathogenicity of HSV-2 [ 135 , 148 , 149 , 150 ]. HSV-2 reactivation, in turn, may predispose the FGT to HIV primo-infection by facilitating the inflammatory infiltration of CD4-positive T lymphocyte cells in the FGT [ 141 ]. In Rio de Janeiro, Brazil, one investigation showed a high frequency of HHV-2/HIV coinfection in patients with recurrent and primary genital infections [ 149 , 151 ].…”

Development of a reverse transcription droplet digital PCR (RT-ddPCR) assay for sensitive detection of simian immunodeficiency virus (SIV)

“…Additional advantages include higher quantification precision, especially at lower target template copy numbers, as well as greater multiplexing ability because of digital PCR's unique amplitude or ratiobased higher order multiplexing [21]. Digital PCR has also been widely used in virus/pathogen analysis [22,23], in addition to cancer mutation detection [24][25][26][27], GMO screening [28], gene and miRNA expression testing, copy number variation (CNV) determination [29][30][31], as well as nucleic acid reference standard and NGS library quantification [32].…”