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Journal of Virology, September 2002, p. 9069-9078, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9069-9078.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Overexpression of Interleukin-2 by a Recombinant Herpes Simplex Virus Type 1 Attenuates Pathogenicity and Enhances Antiviral Immunity

Homayon Ghiasi,1,2* Yanira Osorio,1 Guey-Chuen Perng,1 Anthony B. Nesburn,1,2 and Steven L. Wechsler1,2

Ophthalmology Research, Cedars-Sinai Burns & Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048,1 Department of Ophthalmology, UCLA School of Medicine, Los Angeles, California 900242

Received 8 January 2002/ Accepted 10 June 2002

The expression of interleukin-2 (IL-2) has been implicated in the modulation of the outcome of ocular infection with herpes simplex virus type 1 (HSV-1); however, its effects remain controversial. To clarify the role of IL-2, we constructed a recombinant HSV-1 (HSV-IL-2) that expresses two copies of the murine IL-2 gene under the control of the latency-associated transcript (LAT) promoter of HSV-1 in a LAT-negative virus. In tissue culture, the replication of the HSV-IL-2 was 100-fold lower than that of the wild-type virus at a low multiplicity of infection (MOI). Addition of recombinant anti-IL-2 polyclonal antibody markedly enhanced HSV-IL-2 replication in tissue culture. In the 7-day period after ocular infection of BALB/c mice, the replication of HSV-IL-2 was significantly lower than that of wild-type virus in tear cultures, whole eyes, and brain, but was equivalent to wild-type replication in the trigeminal ganglia. Ocular challenge of BALB/c mice with HSV-IL-2 alone, at an MOI that resulted in only 13% survival when parental virus was used, was associated with 90% survival. This decrease in virulence was further shown to be attributable to the expression of IL-2 by coinfection of mice with HSV-IL-2 and the parental virus. This resulted in a decrease in virulence of the parental virus (5% survival when administered alone versus 50% survival on coinfection with HSV-IL-2). The survival of HSV-IL-2-infected mice was compromised by depletion of either IL-2, CD4+, or CD8+ T cells (50% survival) and abolished completely by depletion of both T-cell subtypes. Moreover, depletion of CD4+ T cells, CD8+ T cells, or both increased the titers of HSV-IL-2 in the tears, eyes, trigeminal ganglia, and brains of infected mice, so that titers were equivalent to or higher than that of the parental virus. These results suggest that IL-2 expression by recombinant HSV-1 reduces virulence and that depletion of IL-2 or T cells increases virulence in HSV-1-infected mice.

* Corresponding author. Mailing address: Ophthalmology Research, Davis Bldg., Rm. 5072, Cedars-Sinai Research Institute, 8700 Beverly Blvd., Los Angeles, CA 90048. Phone: (310) 423-0593. Fax: (310) 423-0225. E-mail: ghiasih{at}CSHS.org.

Journal of Virology, September 2002, p. 9069-9078, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9069-9078.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zandian, M., Belisle, R., Mott, K. R., Nusinowitz, S., Hofman, F. M., Ghiasi, H. (2009). Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2. IOVS 50: 3275-3282 [Abstract] [Full Text]  


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