DEVELOPMENT OF A MONKEY MODEL FOR TESTING OF ANTIVIRAL AGENTS AGAINST HIV-1

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The development of an animal model system for infection and disease by HIV-1 is essential for AIDS vaccine studies and intervention. Currently, the only animal species which can be infected by HIV-1 is the chimpanzee; however, no disease is produced. Due to the enormous cost of maintaining a chimpanzee and the fact that this cannot be a disease model, a better model is sought. We have investigated infection, replication, persistence and clinical changes of HIV-1 in pig-tail macaques. In addition studies are underway to characterize a novel HIV-1/SIV chimeric virus, constructed in our laboratory, for its potential to replicate in pig-tail and rhesus monkeys. Four monkeys were inoculated with two isolates of HIV-1 which differ in their env regions: two monkeys designated as PT86 and PT99 received LAV, which is similar in its env to the laboratory adapted strain, HIV-1 IIIB; and two monkeys designated as PT87 and PT89 received a primary isolate (< 4 passages) which is similar in its env region to the MN strain, which represents the majority of North American HIV-1 isolates. Only PT86 and PT99 seroconverted. In case of PT86, an increasing antibody titer against all the HIV-1 proteins was seen by Western Blot analysis which has remained high at 68 weeks post inoculation (PI). Neutralizing antibodies developed at 6 weeks PI. From the early test time points, infectious HIV-1 was isolated from PBMCs at 4 weeks PI. PCR analysis of PBMCs indicated RNA expression at early time points (4, 6, 8 weeks PI) and again at 40 and 52 weeks PI. At 84 weeks PI, although PT86 has remained clinically healthy, a downward trend in CD4/CD8 may be occurring. In case of PT99, antibodies to only the env proteins were detected; however no virus has been isolated and the CD4/CD8 is stable. These results indicated that LAV infected and replicated in PT86 whereas no evidence of replication was seen in PT99. We have further analyzed the persistence of HIV-1 sequences in the inoculated monkeys. The results of DNA PCR using HIV-1 gag primers indicated that HIV-1 sequences were detected in the PBMCs of PT86 at all time points tested for up to about a year post-inoculation (last time confirmed) whereas the sequences in PT99 were consistently detected at early time points and then sporadically. In case of PT 87 and PT 89 HIV-1 sequences were detected reproducibly only at an early time point indicating infection of the animals but lack of replication. These results confirm that HIV-1 can infect but not replicate efficiently in monkeys. Furthermore, there are host factors that must be considered in selection of animals for development of an AIDS model.