Overexpression of interleukin-2 by a recombinant herpes simplex virus type 1 attenuates pathogenicity and enhances antiviral immunity.
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.
Ophthalmology Research, Cedars-Sinai Burns & Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. ghiasih@CSHS.org
Homayon
H
Ghiasi
Yanira
Y
Osorio
Guey-Chuen
GC
Perng
Anthony B
AB
Nesburn
Steven L
SL
Wechsler
D000818:Animals; D001921:Brain / Q000821:virology; D002460:Cell Line; D005123:Eye / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016849:Keratitis, Herpetic / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000276:immunology; D011995:Recombination, Genetic; D013666:Tears / Q000821:virology; D012668:Trigeminal Ganglion / Q000821:virology; D014774:Virulence; D014779:Virus Replication
D007376:Interleukin-2; D011994:Recombinant Proteins