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 was sought. Based upon a report from the Washington Primate Research Center, studies were undertaken to investigate HIV-1 infection in pig-tail 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 has thusfar been seen in PT99. Studies are underway to analyze infection of PT87 and PT89 by the primary HIV-1 isolate. To achieve HIV-1 disease in monkeys, a high level of persistent virus infection must be established. Thus, studies are in progress to analyze various host factors and viral determinants contributing towards the inability of HIV-1 to establish a persistent high level infection in monkeys. One approach has been construction of a novel recombinant HIV-1 DNA in which the nef and LTR genes have been substituted by SIV239, a pathogenic SIV isolate. This novel virus, designated as SHIV-LTR has proven to replicate in monkeys cells at a higher efficiency than the parent HIV-1. Studies are being performed to analyze replication and disease potential of SHIV-LTR virus in monkeys.