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 that encode the HIV-1 envelope (SHIV). 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 that we have acquired during the past few years, we have generated a recombinant viruses, named simian tropic HIV (stHIV), that are almost entirely derived from HIV-1 but can replicate very efficiently in primary rhesus and pigtailed macaque cells in vitro. Our preliminary data show that stHIV variants are able to replicate at low levels in rhesus and high levels in pigtailed macaques in vivo.
The aims of this proposal are to generate improved derivatives of stHIV with enhanced ability to replicate and cause AIDS in animals and to use these viruses to study HIV-1 pathogenesis in vivo. First, we will expand our very recent findings that an stHIV variant can replicate efficiently in pigtailed macaques and derive a molecular clone of this virus that consistently replicates efficiently in pigtailed macaques in vivo. Based on this virus we will generate R5-tropic variants and initiate mucosal transmission studies. Second, we will reduce the SIVMAC sequences present in stHIV constructs by generating minimally mutated HIV-1 proteins that can confer resistance to macaque restriction factors. Third, we will determine the role of SIVMAC proteins in stHIV replication in rhesus macaques. Finally, we will use the stHIV model to assess the role of HIV-1 accessory proteins in virus replication in vivo. Ultimately, we will generate stHIVs that closely resemble HIV-1 strains that circulate in humans and cause AIDS in an animal model. If successful, these studies should revolutionize the preclinical exploration and development of AIDS therapeutics and vaccines. ? ?
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 developed novel chimeric viruses based on HIV-1 and are proposing to test their utility as an HIV-1 infection model in monkeys and to generate additional HIV-1-derived viruses. 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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