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167 Use of the Nonpathogenic Rev-Independent SIV to Dissect Correlates of Protective Immunity
A. von Gegerfelt1, V. Liska2, M. Marthas3, P. Markham4, N. Miller5, R. Ruprecht2, and B. K. Felber*1
1NCI at Frederick, MD, USA; 2Dana-Farber Cancer Inst., Boston, MA, USA; 3California Regional Primate Res. Ctr., Davis, USA; 4Advanced BioScience Labs, Inc., Kensington, MD, USA; and 5NIAID, NIH, Bethesda, MD, USA
Background: Rev is the key viral factor that is essential for the transport of the unspliced RRE-containing RNA from the nucleus to the cytoplasm. We have demonstrated that the Rev/RRE system of SIV and HIV-1 can be replaced by the type D retrovirus RNA transport element CTE, which is the binding site for the cellular RNA export factor NXF1. Rev-independent Nef(() SIV strains can chronically infect juvenile rhesus macaques, inducing a persistent humoral immune response.
Results: We found that the Rev-independent SIV strains have attenuated growth properties in rhesus macaques independent of the presence of Nef. Infection of neonate and juvenile macaques by the Rev-independent Nef(+) and Nef(() SIV did not induce any signs of immune dysfunction or disease during the 2(4 years of follow-up. These data demonstrate that Rev/RRE regulatory mechanism is required for high levels of virus propagation and that this control mechanism plays an important role in the pathogenicity of SIV. Attenuated strains of SIV provide a unique tool to dissect cellular and viral determinants that contribute to disease development. Juvenile macaques infected with this attenuated SIV strain developed antiviral humoral and cellular responses maintained over 4 years. To examine whether these attenuated virus strains are able to induce a protective immune response, we challenged 6 vaccinated animals with the pathogenic SIVmac251. All animals showed greatly reduced and controlled viremia with no changes in hematological parameters and no signs immune dysfunction over 1 to 1 1/2 years of follow-up.
Conclusions: The replacement of Rev/RRE provides a novel approach to fundamentally alter the virulence of a pathogenic SIV. These studies will provide critical information about the establishment and maintenance of host immune responses during chronic retroviral infections in the absence of pathogenicity.
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