Infection of BALB/c mice with a herpes simplex virus type 1 recombinant virus expressing IFN-gamma driven by the LAT promoter.
A recombinant herpes simplex virus type 1 expressing murine interferon-gamma (IFN-gamma) was constructed (HSV-IFN-gamma) to study the effect of IFN-gamma expression on HSV-1 infection of mice. HSV-IFN-gamma was created by inserting the gene for murine IFN-gamma under the control of the latency-associated transcript (LAT) promoter in a LAT-negative recombinant virus. ELISA analysis confirmed that the recombinant virus expressed high levels of IFN-gamma in tissue culture. The recombinant HSV-IFN-gamma had reduced virulence compared with the wild-type and LAT(-) parental strains as judged by death following ocular and ip infections in BALB/c mice. Replication of HSV-IFN-gamma was wild type in tissue culture and mouse eyes. In addition, peak HSV-IFN-gamma titers in mouse trigeminal ganglia (TG) and brain were similar for all viruses, although HSV-IFN-gamma appeared in the TG and brains of ocularly infected mice earlier than either parental virus. Following stimulation with UV-inactivated virus, lymphocytes from HSV-IFN-gamma-infected mice appeared to produce a steady level of interleukin-2 (IL-2) and IFN-gamma throughout the first week of infection, while the IL-2 and IFN-gamma levels in lymphocytes from wild-type and the LAT-negative parental virus, dLAT2903, varied over time. Also in contrast to lymphocytes from wild-type and dLAT2903-infected mice, lymphocytes from HSV-IFN-gamma-infected mice produced no detectable IL-4. Following stimulation with recombinant IFN-gamma (rIFN-gamma), lymphocytes from HSV-IFN-gamma-infected mice produced higher levels of IFN-gamma, as compared to lymphocytes from control virus-infected mice. Finally, CTL and cell proliferation induced by HSV-IFN-gamma were similar to those of both parental viruses. Thus, this report demonstrates that (i) HSV-IFN-gamma had reduced neurovirulence, despite having enhanced replication in the TG of infected mice; (ii) HSV-IFN-gamma did not enhance CTL activity above that seen in wild-type infected mice; and (iii) HSV-IFN-gamma induced a T(H)1 pattern of cytokine response.
Ghiasi
Homayon
H
Ophthalmology Research, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California 90048, USA. ghiasih@cshs.org
Osorio
Yanira
Y
Hedvat
Yahya
Y
Perng
Guey Chuen
GC
Nesburn
Anthony B
AB
Wechsler
Steven L
SL
D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D002455:Cell Division; D002460:Cell Line; D005123:Eye / Q000276:immunology / Q000821:virology; D005260:Female; D015870:Gene Expression; D006561:Herpes Simplex / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D013666:Tears / Q000276:immunology / Q000821:virology; D012668:Trigeminal Ganglion / Q000276:immunology / Q000473:pathology / Q000821:virology; D014774:Virulence; D014779:Virus Replication
D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma