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 virus, named simian tropic HIV (stHIV), that is almost entirely derived from HIV-1 but can replicate very efficiently in primary rhesus macaque cells in vitro. stHIV expresses only two proteins from SIVMAC that enable it to replicate in rhesus macaque cells in vitro and to infect rhesus macaques and replicate at low levels in vivo.
The aim of this proposal is to generate improved derivatives of stHIV with enhanced ability to replicate and cause AIDS in animals. First, we will determine whether additional SIVMAC accessory proteins have a role in virus replication in vivo by introducing them into stHIV constructs. Second, we will explore an initial finding which suggests that a simple manipulation of HIV-1 should allow avoidance of restriction factors in pigtailed macaques. Third, 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. 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. Relevance to public health 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.
|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|
|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 90:6918-35|
|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 TRIM5Î±-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|
|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|
|Hatziioannou, Theodora; Bieniasz, Paul D (2011) Antiretroviral restriction factors. Curr Opin Virol 1:526-32|
|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|
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