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Journal of Virology, August 1999, p. 6319-6326, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation of Intracerebral Injection in Nonhuman Primates

William D. Hunter,1,dagger Robert L. Martuza,1 Frank Feigenbaum,1 Tomoki Todo,1 Toshihiro Mineta,1,Dagger Takahito Yazaki,1,§ Masahiro Toda,1,parallel Joseph T. Newsome,3 R. Craig Platenberg,4 Herbert J. Manz,5 and Samuel D. Rabkin1,2,*

Departments of Neurosurgery,1 Microbiology and Immunology,2 Radiology,4 and Pathology5 and Division of Comparative Medicine,3 Georgetown University Medical Center, Washington, D.C. 20007

Received 12 February 1999/Accepted 16 April 1999

This study examined the safety of intracerebral inoculation of G207, an attenuated, replication-competent herpes simplex virus type 1 (HSV-1) recombinant, in nonhuman primates. Sixteen New World owl monkeys (Aotus nancymae [karyotype 1, formerly believed to be A. trivirgatus]), known for their exquisite susceptibility to HSV-1 infection, were evaluated. Thirteen underwent intracerebral inoculation with G207 at doses of 107 or 109 PFU, two were vehicle inoculated, and one served as an infected wild-type control and received 103 PFU of HSV-1 strain F. HSV-1 strain F caused rapid mortality and symptoms consistent with HSV encephalitis, including fever, hemiparesis, meningitis, and hemorrhage in the basal ganglia. One year after G207 inoculation, seven of the animals were alive and exhibited no evidence of clinical complications. Three deaths resulted from nonneurologic causes unrelated to HSV infection, and three animals were sacrificed for histopathologic examination. Two animals were reinoculated with G207 (107 PFU) at the same stereotactic coordinates 1 year after the initial G207 inoculation. These animals were alive and healthy 2 years after the second inoculation. Cerebral magnetic resonance imaging studies performed both before and after G207 inoculation failed to reveal radiographic evidence of HSV-related sequelae. Despite the lack of outwardly observable HSV pathology, measurable increases in serum anti-HSV titers were detected. Histopathological examination of multiple organ tissues found no evidence of HSV-induced histopathology or dissemination. We conclude that intracerebral inoculation of up to 109 PFU of G207, well above the efficacious dose in mouse tumor studies, is safe and therefore appropriate for human clinical trials.

* Corresponding author. Mailing address: Department of Neurosurgery, Georgetown University Medical Center, 3970 Reservoir Rd. NW, Washington, DC 20007. Phone: (202) 687-8047. Fax: (202) 687-3046. E-mail: rabkins{at}odrge.odr.georgetown.edu.

dagger Present address: Department of Neurosurgery, University of Wisconsin, Madison, WI 53792.

Dagger Present address: Department of Neurosurgery, Saga Medical School, Saga 849, Japan.

§ Present address: Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160, Japan.

parallel Present address: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160, Japan.

Journal of Virology, August 1999, p. 6319-6326, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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