SIV infection of rhesus macaques is the est animal model for HIV infection and Aids in humans. Studies in this animals model have demonstrated the importance of the nef gene in pathogenesis. Macaques infected with SIVmac239 carrying a deletion in the nef gene (SIVDnef) remained healthy for more than 3 years after infection; in addition animals were protected against challenge with high doses of virulent SIVmac251. Taken together these assessments of SIVDnef in vivo support the notion that this virus is a candidate for a live attenuated vaccine. However, this virus persists indefinitely in macaques, does not protect under one year post-vaccination and is pathogenic to enonates, therefore limiting its potential use as a vaccine. Interferon-gamma inducing factor (IGIF) is a recently discovered cytokine that induces the production of IFN-g, GM-CSF, decreases the production of IL-10 and activates NK ells. These findings and the observation that murine IGIF selectively activates TH- 1 clones, points to the possibility of a Type-1 immune response. The investigator previously constructed a recombinant SIVmac239 clone with a deletion in nef and expressing IFN-g (SIVHyIFN) and demonstrated that compared to SIVDnef, this virus generated a reduced virus load in juvenile macaques and conferred greater resistance to challenge with virulent SIVmac251. Moreover, they demonstrated that this virus was not pathogenic to neonatal macaques. Now they have cloned the macaque IGIF gene and constructed a recombinant virus that carries this gene (SIVHyIGIF). In the present proposal the investigator wishes to study the virologic and immunologic effects of IGIF expression in the context of a retroviral infection and potential vaccine use in macaques. These experiments may provide additional evidence to support the hypothesis that the immune system can be regulated to fight insults by providing the appropriate cytokines at the right times.
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| Giavedoni, Luis D; Velasquillo, M Cristina; Parodi, Laura M et al. (2002) Expression of IL-18 by SIV does not modify the outcome of the antiviral immune response. Virology 303:327-37 |
| Giavedoni, L D; Velasquillo, M C; Parodi, L M et al. (2000) Cytokine expression, natural killer cell activation, and phenotypic changes in lymphoid cells from rhesus macaques during acute infection with pathogenic simian immunodeficiency virus. J Virol 74:1648-57 |
