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 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 simian tropic HIV (stHIV) variants 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 deriving novel viral clones that are consistently pathogenic in immunologically intact animals. We will also derive stHIV variants based on HIV-1 strains circulating in humans and ultimately variants for mucosal transmissions. To achieve these aims our studies will include a detailed characterization of viral RNA splicing and functional characterization of in vivo-adapted viral proteins. Additionally, we will generate an stHIV variant where 100% of the sequence is derived from HIV-1 strains by engineering an HIV-1 Vif proteins that can counteract a major species-specific barrier to virus replication: macaque APOBEC3 proteins. Finally, we aim to 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 variants with the desired properties, 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 (when their immune system is manipulated) and we are now proposing to further develop this new HIV-1 infection model, test its utility and to generate additional HIV-1-derived viruses that can replicate and cause disease in immunologically intact 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.
| Bohn, Jennifer A; Thummar, Keyur; York, Ashley et al. (2017) APOBEC3H structure reveals an unusual mechanism of interaction with duplex RNA. Nat Commun 8:1021 |
| Del Prete, Gregory Q; Keele, Brandon F; Fode, Jeannine et al. (2017) A single gp120 residue can affect HIV-1 tropism in macaques. PLoS Pathog 13:e1006572 |
| Saito, Akatsuki; Henning, Matthew S; Serrao, Erik et al. (2016) Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo. J Virol 90:6918-6935 |
| Li, Hui; Wang, Shuyi; Kong, Rui et al. (2016) Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A 113:E3413-22 |
| 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; Evans, David T (2012) Animal models for HIV/AIDS research. Nat Rev Microbiol 10:852-67 |
| Hatziioannou, Theodora; Bieniasz, Paul D (2011) Antiretroviral restriction factors. Curr Opin Virol 1:526-32 |
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