Overcoming Host Restriction Factors to Develop Better Animal Models for HIV/AIDS

Information

  • Research Project
  • 9087138
  • ApplicationId
    9087138
  • Core Project Number
    R01AI078788
  • Full Project Number
    4R01AI078788-09
  • Serial Number
    078788
  • FOA Number
    PA-11-260
  • Sub Project Id
  • Project Start Date
    4/1/2008 - 16 years ago
  • Project End Date
    6/30/2018 - 6 years ago
  • Program Officer Name
    SANDERS, BRIGITTE E.
  • Budget Start Date
    7/1/2016 - 8 years ago
  • Budget End Date
    6/30/2017 - 7 years ago
  • Fiscal Year
    2016
  • Support Year
    09
  • Suffix
  • Award Notice Date
    6/17/2016 - 8 years ago

Overcoming Host Restriction Factors to Develop Better Animal Models for HIV/AIDS

DESCRIPTION (provided by applicant): 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. 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 recombinant viruses, named simian tropic HIV (stHIV), 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 generating infectious molecular clones that are consistently pathogenic following mucosal challenges in both pigtail and rhesus macaques and are based on HIV-1 strains circulating in humans. To achieve these aims our studies will include a more detailed characterization of restriction factor polymorphism and activity in macaques and how these drive virus evolution in animals. Additionally, we will 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, an advance that has the potential to transform non- human primate models for HIV-1 drug and vaccine development.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    4
  • Direct Cost Amount
    531213
  • Indirect Cost Amount
    243325
  • Total Cost
    774538
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:774538\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    AIP
  • Study Section Name
    AIDS Immunology and Pathogenesis Study Section
  • Organization Name
    AARON DIAMOND AIDS RESEARCH CENTER
  • Organization Department
  • Organization DUNS
    786658872
  • Organization City
    NEW YORK
  • Organization State
    NY
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    100169102
  • Organization District
    UNITED STATES