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Session 52 Poster Session Pathogenesis Studies in Animal Models Session Time: 4:30-6:30 pm Room 4E-F

333-W. Rev-Independent SIV as Model to Study Pathogenic Mechanisms in Neonatal and Juvenile Rhesus Macaques A. von Gegerfelt1, V. Liska2, M. Marthas3, H. McClure4, D. Montefiori5, P. Li2, P. Markham6, N. Miller7, R. Ruprecht2, and B. K. Felber*1 1NCI, NIH, Frederick, MD; 2Dana-Farber Cancer Inst. and Harvard Med. Sch., Boston, MA; 3California Regional Primate Res. Ctr., Davis; 4 Yerkes Regional Primate Res. Ctr., Emory Univ., Atlanta, GA; 5Duke Univ. Med. Ctr., Durham, NC; 6 Advanced BioSci. Labs., Inc., Kensington, MD; and 7NIAID, NIH, Bethesda, MD Background: The viral protein Rev is the key viral factor essential for the export of the subset of unspliced and partially spliced lentiviral mRNAs and the production of structural proteins. Rev and its RNA binding site RRE can be replaced in both HIV and SIV by the constitutive RNA transport element CTE of the simian type D retroviruses. We addressed the question whether change of the conserved Rev regulation affects the pathogenicity of SIV. Methods: Multiple point mutations were introduced to destroy rev and RRE without affecting the overlapping tat and env open reading frame in SIVmac239. Virus stocks were used to infect neonatal, juvenile, and adult rhesus macaques. Hematological, virological, and immunological parameters were monitored. Results: We used neonatal macaques as a sensitive animal model to evaluate the pathogenicity of a pair of SIV mutant strains generated from Rev-independent molecular clones of SIVmac239 which only differ in the presence of nef open reading frame. After high primary viremia all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally and none showed any signs of immune dysfunction or disease during follow-up ranging from 2.3-4 years. In addition, infection of juvenile and adult macaques by the Rev-independent SIV strains also did not induce any signs of immune dysfunction or disease. Therefore, the Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef. We further found that all animals mounted persistent humoral and cellular immune responses. Conclusions: Replacement of Rev-RRE by the CTE provides a different approach to dramatically lower the virulence of a pathogenic lentivirus. These data demonstrate that Rev regulation plays an important role in the pathogenicity of SIV. These non-pathogenic strains of SIV serve as a unique tool in the experimentally infected rhesus macaque to dissect cellular and viral determinants that contribute to disease development. Our data further suggest that anti-retroviral strategies leading to even a partial block of Rev function may modulate disease progression in HIV-infected individuals.

©2002 9th Conference on Retroviruses and Opportunistic Infections