The lentiviruses all encode for a Vif protein that has been shown to interact with members of the apolipoprotein mRNA-editing, catalytic polypeptide-like 3 (APOBEC3) superfamily of proteins. The APOBEC3 proteins are cytidine deaminases that are thought to play an important role in innate anti-viral immunity. Humans and macaques both encode for seven APOBEC3 genes (A3A, A3B, A3C, A3D, A3F, A3G, and A3H). The APOBEC3 proteins can be broadly divided into the single deaminase domain (A3A, A3C, and A3H) and double deaminase domain proteins (A3B, A3D, A3F, and A3G). Human A3A (hA3A) does not restrict the replication of HIV-1?vif in 293 cells or HeLa cells but has recently been shown to inhibit replication of HIV?vif in macrophage-derived macrophages (MDM). In contrast, rhA3A from rhesus macaques is capable of restricting both HIV-1 and SHIV (expressing the SIV Vif). We recently have assessed the ability of other non-human primate A3A proteins to restrict HIV-1 and HIV-1?vif. We present preliminary data that the A3A protein from the Old World monkey, Colobus guereza (the mantled guereza, colA3A), not only inhibits the replication of HIV-1 and HIV-1?vif but also inhibits virus production in producer cells. Our preliminary studies indicate that the colA3A inhibits by a novel post-entry mechanism and, but not after, proviral integration.
In Specific Aim 1, we propose to determine the mechanism though which colA3A inhibits HIV-1 replication and assess the molecular determinants involved.
In Specific Aim 2, we propose to determine whether expression of colA3A in human CD4+ T cells and macrophages can restrict HIV-1 in cells it naturally infects. The proposed studies will provide mechanistic insight into this novel mechanism of A3 protein inhibition of HIV-1, which could serve as a new anti-viral strategy against HIV-1.

Public Health Relevance

The Vif protein of HIV-1 is required to counteract select innate antiviral factors of the APOBEC3 superfamily. We have shown that the A3A protein from an Old World Monkey can restrict the replication of wild type (non- gene deleted) by a novel mechanism. Thus, better understanding of the mechanism through which this A3A protein restricts the replication of HIV-1 will be useful in designing future anti-retroviral therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Sanders, Brigitte E
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University of Kansas
Schools of Medicine
Kansas City
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Wang, Yaqiong; Wang, Zekun; Pramanik, Ankita et al. (2016) A chimeric human APOBEC3A protein with a three amino acid insertion confers differential HIV-1 and adeno-associated virus restriction. Virology 498:149-163
Wang, Yaqiong; Schmitt, Kimberly; Guo, Kejun et al. (2016) Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer. J Gen Virol 97:1-17
Guo, Kejun; Halemano, Kalani; Schmitt, Kimberly et al. (2015) Immunoglobulin VH gene diversity and somatic hypermutation during SIV infection of rhesus macaques. Immunogenetics 67:355-70
Katuwal, Miki; Wang, Yaqiong; Schmitt, Kimberly et al. (2014) Cellular HIV-1 inhibition by truncated old world primate APOBEC3A proteins lacking a complete deaminase domain. Virology 468-470:532-44
Schmitt, Kimberly; Guo, Kejun; Katuwal, Miki et al. (2013) Lentivirus restriction by diverse primate APOBEC3A proteins. Virology 442:82-96