The production of type-1 interferons (IFNs) by the host innate immune system presents the first barrier against viral infection. IFNs are innate immune factors that upregulate expression of hundreds of IFN- stimulated genes (ISGs), which results in induction of an ?antiviral state?. A small group of ISGs encode proteins that restrict HIV-1 and SIV replication and are referred to as ?restriction factors?. Restriction factors are less active against wild-type viruses replicating in their natural host but act as potent barriers against cross- species transmission. Macaque model systems are critical gatekeepers for testing HIV-1 prevention methods and for studies of HIV-1 transmission and pathogenesis. HIV-1 does not persistently infect macaques due to restriction by several macaque-specific restriction factors necessitating the use of chimeric SIV/HIV-1 viruses (SHIVs). Existing SHIV/macaque models typically employ SHIVs that encode HIV-1 sequences from viruses amplified in culture and further adapted in macaques (adapted SHIVs). Development of SHIVs encoding circulating HIV-1 variants derived directly from infected humans (circulating SHIVs) has been challenging as these SHIVs replicate poorly in macaque cells, if at all. While some host restrictions to HIV-1 replication in macaques have been defined, there is limited information on macaque-specific restriction factors that limit replication of circulating HIV-1 variants. Our preliminary results suggest that circulating SHIVs replicate poorly and are potently inhibited by macaque-specific IFN responses despite encoding the SIV antagonists of known restriction factors. In contrast, SHIVs encoding adapted HIV-1 sequences are resistant to IFN inhibition. Thus, this research proposal will characterize the host-viral interactions that selectively restrict replication of circulating SHIVs. During the mentored phase (K99): 1) the viral determinants of macaque-adapted SHIVs that confer resistance to IFN are expected to be defined, and 2) macaque-specific restriction factor(s) against circulating HIV-1 variants is expected to be identified. During the independence phase (R00): 1) characterization of the viral determinants of macaque-adapted SHIVs will be performed. The ability of the adaptive mutations to infect targets cells at the sites of mucosal transmission will be determined, 2) a novel example of cross-species host-viral interaction will be explored by characterizing the post-transcriptional regulation of HIV-1 envelope gene-expression in macaque lymphocytes, and 3) the mechanism of restriction of the macaque-specific restriction factor will be elucidated. Upon completion, this research proposal will successfully integrate the features of clinically relevant circulating HIV-1 variants with species-specific host innate immune system to help understand how macaque- specific IFN responses restrict circulating SHIVs.
HIV-1 does not replicate in nonhuman primates due to restrictions presented by the host innate immune system, thus significantly limiting the animal models for vaccine and therapeutic efforts. Engineered attempts to overcome these host restrictions have not been fully successful because the host-virus interactions are not well characterized. The proposed studies will characterize how the globally circulating HIV-1 viruses interact with nonhuman primate innate immune responses. Understanding the virus and host determinants necessary for these interactions will significantly improve challenge viruses for vaccine and therapeutic approaches.
| Nahabedian, John; Sharma, Amit; Kaczmarek, Maryska E et al. (2017) Owl monkey CCR5 reveals synergism between CD4 and CCR5 in HIV-1 entry. Virology 512:180-186 |
| Boyd, David F; Sharma, Amit; Humes, Daryl et al. (2016) Adapting SHIVs In Vivo Selects for Envelope-Mediated Interferon-? Resistance. PLoS Pathog 12:e1005727 |
