Herpes Simplex Virus Type 1 Latency-Associated Transcript Expression Protects Trigeminal Ganglion Neurons from Apoptosis

Abstract

FACS). FACS analysis revealed CD8؉ T cells in the trigeminal ganglia by day 7, with more being present in 17-than 17 N/H-infected trigeminal ganglia (6.22% versus 3.5%) and a decrease in number through day 30 (2.7% to 1.2%). To detect apoptotic CD8 ؉ T cells, sections were assayed by TUNEL and stained for CD8 ؉ T cells. By day 7, ϳ10% of CD8 ؉ T cells in both 17-and 17 N/H-infected trigeminal ganglia had undergone apoptosis. By day 30, 58% and 74% of all T cells had undergone apoptosis in 17-and 17 N/H-infected trigeminal ganglia, respectively. Furthermore, no HSV strain 17-infected trigeminal ganglion neurons were apoptotic, but 0.087% of 17⌬Sty and 0.98% of 17 N/H-infected neurons were apoptotic. We conclude that the antiapoptotic effect of LAT appears to require the LAT promoter, with most of the antiapoptotic effect mapping within the StyI (؉447) to the HpaI (؉1667) region and a minor contribution from the upstream StyI (؉76) to StyI (؉447) region.

The functions of herpesvirus-encoded microRNAs

“…Expressed exclusively within infected neurons, LATs are the only transcript thought to be expressed by HSV-1 during latency [9]. Although no function has been deWnitively shown for LAT, it has been suggested to be involved in the restriction of viral trans-activating proteins and in blocking cellular apoptosis in response to infection, both by unknown mechanisms [10,11] (Fig. 1).…”

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

“…LAT is important for wild-type (WT) levels of spontaneous and induced reactivation from latency (9,10). The LAT region plays a role in blocking apoptosis in rabbits (11) and mice (12). Antiapoptosis activity appears to be the critical LAT function involved in enhancing the latency-reactivation cycle because LAT-deficient [LAT(Ϫ)] virus can be restored to full wild-type reactivation levels by substitution of different antiapoptosis genes (i.e., baculovirus inhibitor of apoptosis protein gene [cpIAP] or cellular FLICE-like inhibitory protein [FLIP]) (13)(14)(15).…”

Introducing point mutations into the ATGs of the putative open reading frames of the HSV-1 gene encoding the latency associated transcript (LAT) reduces its anti-apoptosis activity

“…LAT plays an important role in the HSV latency-reactivation cycle since LAT null mutants have significantly reduced reactivation phenotypes in mice and rabbits while otherwise having wild-type like replication [5][6][7][8][9][10][11]. LAT has anti-apoptosis activity [12][13][14][15][16][17][18][19]. Mutants in which LAT is replaced by an alternative anti-apoptosis gene have efficient, wild-type like reactivation phenotypes [20][21][22], indicating that LAT's anti-apoptosis activity is sufficient to account for LAT's ability to support the wild-type reactivation phenotype in experimental animal models.…”