Herpes Simplex Virus Type 1 Latency-Associated Transcript Gene Promotes Neuronal Survival

Abstract

A complex interaction has evolved between the host's peripheral nervous system (PNS) and herpes simplex virus type 1 (HSV-1). Sensory neurons are permissive for viral replication, yet the virus can also enter a latent state in these cells. The interplay of viral and neuronal signals that regulate the switch between the viral lytic and latent states is not understood. The latency-associated transcript (LAT) regulates the establishment of the latent state and is required for >65% of the latent infections established by HSV-1 (R. L. Thompson and N. M. Sawtell, J. Virol. 71:5432-5440, 1997). To further investigate how LAT functions, a 1.9-kb deletion that includes the entire LAT promoter and 827 bp of the 5 end of the primary LAT mRNA was introduced into strain 17syn؉. The wild-type parent, three independently derived deletion mutants, and two independently derived genomically rescued variants of the mutants were analyzed in a mouse ocular model. The number of latent sites established in trigeminal ganglion (TG) neurons was determined using a single-cell quantitative PCR assay for the viral genome on purified TG neurons. It was found that the LAT null mutants established ϳ75% fewer latent infections than the number established by the parental strain or rescued variant. The reduced establishment phenotype of LAT null mutants was due at least in part to a dramatic increase in the loss of TG neurons in animals infected with the LAT mutants. Over half of the neurons in the TG were destroyed following infection with the LAT mutants, and this was significantly more than were lost following infection with wild type. This is the first demonstration that the HSV LAT locus prevents the destruction of sensory neurons. The death of these neurons did not appear to be the result of increased apoptosis as measured by a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay. Animals latently infected with the LAT null mutants reactivated less frequently in vivo and this was consistent with the reduction in the number of neurons in which latency was established. Thus, one function of the LAT gene is to protect sensory neurons and enhance the establishment of latency in the PNS.A complex interaction between the virus and the host determines the fate of cells infected by herpes simplex virus type 1 (HSV-1). At the body surface, about 77 known viral lyticphase genes are actively transcribed during productive infection, which is invariably lethal for the cell. Latent infections are characterized by the down regulation of these lytic-phase genes in innervating sensory neurons of the trigeminal ganglia (TG), and these cells survive infection. The continued expression of the latency-associated transcript (LAT) is detectable by in situ hybridization in about 100 to 200 sensory neurons per mouse TG (for review, see references 1 and 87). The discovery of the LAT RNAs over a decade ago led to speculation that that they must play a central role in viral latency (70), but the function(s) of the LAT gene is not yet unde...

Anatomical mapping of human herpesvirus reservoirs of infection

“…Primary HSV-1 infection of immunocompetent persons is characterized by lesions of the oral mucosa, followed by latent persistence within neurons of cervical and cranial nerve sensory ganglia. [3][4][5][6][7][8][9][10][11] In some cases, HSV-1 and HSV-2 can be found in brain tissue. 12 Viral reactivation can lead to recurrent mucocutaneous disease, whereas dissemination may lead to widespread organ involvement, including esophagus, lower gastrointestinal tract, trachea, lungs, brain, eyes, and skin.…”

Herpes Zoster Overlying Recently Placed Central Venous Access Site: A Case Report

“…1,30,31 Multiple pathways likely lead to viral reactivation via transcription of the latent virus, 32 and the process involves specific cytokines, notably IL-6 and tumor necrosis factor alpha, and expression of specific viral proteins such as VP16. [33][34][35][36][37] The concept of local trauma inciting VZV reactivation has been explored. 36 The mechanism in which shingles localizes to an actual incision site is even less clear, but perhaps relates to physiologic changes that occur locally at the site of the procedure, triggering hyperemia and loss of innate immunity.…”

Latence et réactivation du virus de l’herpès simplex de type 1 (HSV-1)

“…Certaines études suggèrent que les LAT auraient une action anti-apoptotique, en inhibant la mort cellulaire induite par l'infection herpétique [26]. Cependant, d'autres observations ne confirment pas l'existence d'un phénomène antiapoptotique et suggèrent que l'action protectrice des LAT serait simplement la conséquence de l'inhibition de l'expression des gènes lytiques [27].…”