Mapping the genetic region coding for herpes simplex virus resistance to mouse interferon  /beta

Abstract

Herpes simplex virus (HSV) ocular virulence has been associated with strain sensitivity to mouse interferon (IFN)-ct/fl. To identifiy the region of the virus genome associated with heightened resistance to this cytokine, intertypic recombinants were constructed using the intact genome of avirulent, IFN-sensitive HSV type 1 (strain 35) and XbaI-digested DNA from virulent, IFNresistant HSV type 2 (strain 186). An intertypic recombinant, designated HSV-R4, was isolated which grew to titres 10-to 100-fold higher than HSV-l(35) in mouse ocular tissue in vivo, and induced stromal keratitis. The recombinant which was several orders of magnitude more resistant to mouse IFN-ct/fl than HSV-l(35) had a genome composed of HSV-l(35) DNA except for a 12 kb fragment (0.15 to 0.23 map units) derived from HSV-2(186). To define the IFN resistance locus further, three overlapping subclones of this 12 kb fragment were constructed from the HSV-2(186) genome and subjected to marker rescue experiments. The cloned BamHI D fragment was the only subclone that promoted HSV-1 (35) ocular growth in vivo. An intertypic recombinant, designated HSV-R(BD), was isolated from the 35 x 186 BamHI D transfection progeny pool. This recombinant, in contrast to HSV-l(35), was several orders of magnitude more resistant to mouse IFN-ct/fl inhibition in vitro, grew 10-to 100-fold better in mouse ocular tissue in vivo, and caused severe necrotizing stromal keratitis in BALB/c mice. Analysis of the recombinant genome indicated that the HSV-2 genetic information responsible for IFN resistance of HSV-R(BD) was located within the BamHI D fragment, most likely mapping to that region containing three partial open reading frames designated UL14, UL15 and UL16. The products encoded by this region remain to be identified.

The BglII-N fragment of herpes simplex virus type 2 contains a region responsible for resistance to antiviral effects of interferon.

“…Moreover, we performed marker rescue experiments to physically map one of the coding regions and found that the BglII-N fragment of HSV-2, which was distinct from the region reported by Su et al (1993) contained an IFN-resistance gene. Together with the results of this and previous reports, we would like to discuss the relationship between the HSV-encoded information and IFN resistance.…”

“…Cayley et al (1984) suggested that HSV inhibits the IFNinduced 2h-5h-oligoadenylate synthetase (2-5A)-RNase L pathway by producing a 2-5A analogue. Su et al (1993) reported that one region of the HSV genome containing three partial open reading frames (ORFs), designated UL14, UL15 and UL16, is associated with IFN resistance. However, the mechanism by which HSV abrogates the anti-HSV effects of IFNs is still unclear.…”

Differential Effect of Murine Alpha/Beta Interferon Transgenes on Antagonization of Herpes Simplex Virus Type 1 Replication

“…Likewise, in vivo studies have determined that IFN-␣/␤ play a dominant role in controlling acute HSV-1 infection (22,26,66,67) and facilitate the adaptive immune response to infection (16). Although it was originally thought that the target of IFN-␣/␤ might include viral protein 16 (13), it has subsequently been suggested that the level of antagonism might be more generalized (52,60).…”

Selective Ablation of Virion Host Shutoff Protein RNase Activity Attenuates Herpes Simplex Virus 2 in Mice

“…Genetic mapping of HSV-1 IFN resistance identified a region that includes the vhs locus (58). HSV-1 vhs deletion mutants show little or no increased sensitivity to type I IFN in vitro (38,59), and their replication in vivo is not significantly affected by IFN-␣/␤ (31).…”