Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study.
The owl monkey (Aotus trivirgatus) has served as the standard non-human primate model of herpes simplex virus-1 (HSV-1) infection because it is highly susceptible to HSV-1 encephalitis. Owl monkeys, however, are expensive, difficult to obtain, and difficult to maintain in captivity, thus greatly hampering the efficiency of preclinical gene therapy trials for brain tumors using HSV-1-based vectors. We have therefore compared the susceptibility of the common marmoset (Callithrix jacchus) with the owl monkey in a model of intracerebral inoculation of wildtype HSV-1 F-strain at increasing titers. The common marmosets consistently succumbed earlier to viral encephalitis than the owl monkeys. The histological evaluation of the common marmoset revealed extensive HSV-1 infection with a concomitant yet less marked inflammatory response compared to the owl monkeys. PCR for HSV-1 demonstrated a similar extra-CNS shedding route in both experimental models. Our findings show that the common marmoset is at least as susceptible to intracerebral HSV-infection as the owl monkey and that it can therefore serve as a valid and reliable experimental model for the important preclinical safety tests of HSV-based therapeutic viral vector constructs in the brain.
Deisboeck
T S
TS
Neurosurgical Service, Massachusetts General Hospital East, Harvard Medical School, Charlestown, MA, USA.
Wakimoto
H
H
Nestler
U
U
Louis
D N
DN
Sehgal
P K
PK
Simon
M
M
Chiocca
E A
EA
Hochberg
F H
FH
D000818:Animals; D001921:Brain / Q000821:virology; D002144:Callithrix / Q000821:virology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D020803:Encephalitis, Herpes Simplex / Q000209:etiology / Q000473:pathology*; D005260:Female; D005822:Genetic Vectors / Q000633:toxicity*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity*; D007668:Kidney / Q000821:virology; D008099:Liver / Q000821:virology; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D015996:Survival Rate