HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most non-human species. Therefore, the most practical animal model of human AIDS consists of infection of rhesus macaques with SIVMAC or chimeras derived from SIVMAC. However, the usefulness of these models is limited by the fact that HIV-1 and SIVMAC are distinct viruses. Based on an understanding of species-specific restriction factors, we have generated recombinant viruses, named simian tropic HIV (stHIV), that are almost entirely derived from HIV-1 but can replicate in pigtailed macaques. During the last funding cycle we have used animal adaptation to develop stHIV isolates that cause AIDS in pigtail macaques. Additionally, we have studied the effects of known restriction factors on stHIV replication and unveiled the activity of novel, as yet unidentified, inhibitors that are induced by IFN? and limit lentiviral replication in a species-specific manner in primary cells.
The aims of this proposal are to further develop stHIV by generating infectious molecular clones that are consistently pathogenic following mucosal challenges in both pigtail and rhesus macaques and are based on HIV-1 strains circulating in humans. To achieve these aims our studies will include a more detailed characterization of restriction factor polymorphism and activity in macaques and how these drive virus evolution in animals. Additionally, we will identify novel IFN!-induced inhibitors that limit stHIV replication in macaque cells and generate stHIV variants that can overcome them. Our preliminary data suggest that these goals are feasible and will lead to the successful development of stHIV, an advance that has the potential to transform non- human primate models for HIV-1 drug and vaccine development.
HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species and current animal models are limited. We have generated novel chimeric viruses based on HIV-1 that can cause AIDS in monkeys and are proposing to further develop this new HIV-1 infection model and test its utility and to generate additional HIV-1-derived viruses that can replicate and cause disease in monkeys. If successful, this proposal will lead to improved animal models for HIV-1 infection and will considerably facilitate the development and testing of drug and vaccine interventions.
|Hatziioannou, Theodora; Del Prete, Gregory Q; Keele, Brandon F et al. (2014) HIV-1-induced AIDS in monkeys. Science 344:1401-5|
|Kane, Melissa; Yadav, Shalini S; Bitzegeio, Julia et al. (2013) MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 502:563-6|
|Bitzegeio, Julia; Sampias, Marissa; Bieniasz, Paul D et al. (2013) Adaptation to the interferon-induced antiviral state by human and simian immunodeficiency viruses. J Virol 87:3549-60|
|Soll, Steven J; Wilson, Sam J; Kutluay, Sebla B et al. (2013) Assisted evolution enables HIV-1 to overcome a high TRIM5*-imposed genetic barrier to rhesus macaque tropism. PLoS Pathog 9:e1003667|
|Hatziioannou, Theodora; Bieniasz, Paul D (2011) Antiretroviral restriction factors. Curr Opin Virol 1:526-32|
|Zhang, Fengwen; Landford, Wilmina N; Ng, Melinda et al. (2011) SIV Nef proteins recruit the AP-2 complex to antagonize Tetherin and facilitate virion release. PLoS Pathog 7:e1002039|
|Zhang, Fengwen; Wilson, Sam J; Landford, Wilmina C et al. (2009) Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe 6:54-67|
|Sauter, Daniel; Schindler, Michael; Specht, Anke et al. (2009) Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host Microbe 6:409-21|
|Hatziioannou, Theodora; Ambrose, Zandrea; Chung, Nancy P Y et al. (2009) A macaque model of HIV-1 infection. Proc Natl Acad Sci U S A 106:4425-9|
|McNatt, Matthew W; Zang, Trinity; Hatziioannou, Theodora et al. (2009) Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. PLoS Pathog 5:e1000300|