Significant new advances were made in developing novel therapeutic strategies to cure chronic retroviral infections. Previous studies in our lab showed that regulatory T cells suppressed anti-viral CD8+ T cell responses in mice chronically infected with Friend retrovirus. Based on this knowledge we used a combination of adoptive lymphocyte transfer and immunomodulatory antibodies designed to render CD8+ T cells resistant to suppression by regulatory T cells. The strategy produced short term reductions in virus loads of greater than 99%. Current studies are focused on improving the longevity of virus load reductions. In addition, our current studies are also optimizing the therapeutic dosing and scheduling protocols and eliminating the requirement for adoptive lymphocyte transfers to achieve virus reductions. We are also actively engaged in determing precisely how the therapeutics affect various aspects of the immune system in terms of understanding both the mechanisms of action and possible safety issues. Progress has also been made in determing how regulatory T cells are induced during infection and how the induction of these cells is affected by vaccination. Important discoveries on the tissue distribution of virus-induced regualtory T cells have also been made that have ramifications for further development of therapeutics. Recent reports indicate that regulatory T cell suppression of CD8+ T cell responses is also occurring in HIV infections in humans and the degree of suppression correlates with viral loads. Thus our mouse model is extremely relvant to human retroviral infections and may lead to new therapies to treat chronic HIV infections.? ? In 2008 collaborative work, we found that Recovery from Friend virus 3 (Rfv3) is encoded by Apobec3. Rfv3 is a single autosomal gene encoding a resistance trait that influences retroviral neutralizing antibody responses and viremia. Despite extensive research for 30 years, the molecular identity of Rfv3 has remained elusive. Apobec3 maps to the same chromosome region as Rfv3 and has broad inhibitory activity against retroviruses, including HIV. Not only did genetic inactivation of Apobec3 convert Rfv3-resistant mice to a susceptible phenotype, but Apobec3 was also found to be naturally disabled by aberrant messenger RNA splicing in Rfv3-susceptible strains. The link between Apobec3 and neutralizing antibody responses highlights an Apobec3-dependent mechanism of host protection that might extend to HIV and other human retroviral infections.
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