Region of herpes simplex virus type 1 latency-associated transcript sufficient for wild-type spontaneous reactivation promotes cell survival in tissue culture

The latency-associated transcript (LAT) is the only abundant herpes simplex virus type 1 (HSV-1) transcript expressed during latency. In the rabbit ey e model, LAT null mutants do not reactivate efficiently from latency. We re cently demonstrated that the LAT null mutant dLAT2903 induces increased lev els of apoptosis in trigeminal ganglia of infected rabbits compared to LAT( +) strains (G.-C. Perng, C. Jones, J. Ciacci-Zarella, M. Stone, G. Henderso n, A. Yokht, S. M. Slanina, F. M. Hoffman, H. Ghiasi, A. B. Nesburn, and C. S. Wechsler, Science 287:1500-1503, 2000). The same study also demonstrate d that a plasmid expressing LAT nucleotides 301 to 2659 enhanced cell survi val of transfected cells after induction of apoptosis. Consequently, we hyp othesized that LAT enhances spontaneous reactivation in part, because it pr omotes survival of infected neurons. Here we report on the ability of plasm ids expressing different portions of the 5' end of LAT to promote cell surv ival after induction of apoptosis, A plasmid expressing the first 1.5 kb of LAT (LAT nucleotides 1 to 1499) promoted cell survival in neuro-2A (mouse neuronal) and CV-1 (monkey fibroblast) cells, A plasmid expressing just the first 811 nucleotides of LAT promoted cell survival less efficiently. Plas mids expressing the first 661 nucleotides or less of LAT did not promote ce ll survival. We previously showed that a mutant expressing just the first 1 .5 kb of LAT has wild-type spontaneous reactivation in rabbits, and a mutan t expressing just the first 811 nucleotides of LAT has a reactivation frequ ency higher than that of dLAT2903 but lower than that of wild-type virus. I n addition, mutants reported here for the first time, expressing just the f irst 661 or 76 nucleotides of LAT, had spontaneous reactivation indistingui shable from that of the LAT null mutant dLAT2903. In summary, these studies provide evidence that there is a functional relationship between the abili ty of LAT to promote cell survival and its ability to enhance spontaneous r eactivation.