Phenotype of a Herpes Simplex Virus Type 1 Mutant That Fails To Express Immediate-Early Regulatory Protein ICP0

Abstract

Herpes simplex virus type 1 (HSV-1) immediate-early (IE) regulatory protein ICP0 is required for efficient progression of infected cells into productive lytic infection, especially in low-multiplicity infections of limitedpassage human fibroblasts. We have used single-cell-based assays that allow detailed analysis of the ICP0-null phenotype in low-multiplicity infections of restrictive cell types. The major conclusions are as follows: (i) there is a threshold input multiplicity above which the mutant virus replicates normally; (ii) individual cells infected below the threshold multiplicity have a high probability of establishing a nonproductive infection; (iii) such nonproductively infected cells have a high probability of expressing IE products at 6 h postinfection; (iv) even at 24 h postinfection, IE protein-positive nonproductively infected human fibroblast cells exceed the number of cells that lead to plaque formation by up to 2 orders of magnitude; (v) expression of individual IE proteins in a proportion of the nonproductively infected cells is incompletely coordinated; (vi) the nonproductive cells can also express early gene products at low frequencies and in a stochastic manner; and (vii) significant numbers of human fibroblast cells infected at low multiplicity by an ICP0-deficient virus are lost through cell death. We propose that in the absence of ICP0 expression, HSV-1 infected human fibroblasts can undergo a great variety of fates, including quiescence, stalled infection at a variety of different stages, cell death, and, for a minor population, initiation of formation of a plaque.

Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

“…However, the number of viral particles capable of transferring GM1 to the HveC-1 cells was probably much greater than the actual amount of infectious virus present in the supernatants. Particle:infectivity ratios for HSV-1 have been determined to range from 10 to 50 or greater (27,28). Virus-cell GM1 transfer for HSV-1(KOS) and gB Ϫ viruses was most efficient at 37°C but also occurred at 23°C but not at 4°C (data not shown).…”

A RING Finger Ubiquitin Ligase Is Protected from Autocatalyzed Ubiquitination and Degradation by Binding to Ubiquitin-specific Protease USP7

“…The IE protein ICP0 has an important role in the mechanisms that govern the switch between lytic and latent infection (reviewed in Refs. [3][4][5]. Although not essential for viral replication, ICP0 increases the probability of the virus entering lytic infection, particularly after low multiplicity infection of human fibroblasts, and in its absence, viral genomes are more likely to become repressed and establish a quiescent infection (5)(6)(7).…”

“…[3][4][5]. Although not essential for viral replication, ICP0 increases the probability of the virus entering lytic infection, particularly after low multiplicity infection of human fibroblasts, and in its absence, viral genomes are more likely to become repressed and establish a quiescent infection (5)(6)(7). ICP0 stimulates the expression of all three classes of viral genes by as yet uncertain mechanisms that correlate with its ability to induce the degradation of a number of cellular proteins (8 -12).…”

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

“…ICP0 agit en inhibant des réponses antivirales, tant au niveau des voies de l'interféron (IFN) qu'au niveau des défenses intrinsèques présentes dans les noyaux avant l'infection [9]. Des mutants d'HSV-1 exprimant une protéine ICP0 inactive ont une moindre probabilité de déclencher une infection lytique, surtout à faible multiplicité [10]. Nous ne pouvons pas décrire ici en détail les multiples activités d'ICP0.…”

“…Nous ne pouvons pas décrire ici en détail les multiples activités d'ICP0. Mais il est important de signaler que cette protéine empêche l'association du génome viral à des protéines nucléaires impliquées dans les défenses intrinsèques de la cellule, dont PML (promyelocytic leukaemia), Sp100, Daxx et ATRX (alpha thalassemia/mental retardation syndrome X-linked) [10,11]. ICP0 interagit aussi avec des histones déacétylases [12] et induit la dégradation de plusieurs protéines centromériques [13], ainsi que celle de protéines participant à la réparation de l'ADN [14].…”