As an obligate intracellular parasite HIV, like all viruses, relies on host-encoded factors to complete its life cycle inside the host cell. However, the virus must also evade recognition by specialized host factors that have evolved specifically to defend cells against viral invasion. Some of the antiviral genes are part of an Interferon-induced transcriptional program that is deployed by the host on sensing of a viral invader. A comprehensive description of host genes that block primate lentiviruses from successfully infecting human cells has evaded characterization with current methodologies.
In Aim 1 we will describe the mechanism of inhibition of HIV-1 and related primate Simian Immunodeficiency Virus (SIV) variants by TRIM34, a TRIM5 paralog we have discovered to specifically target HIV-1 capsid variants and SIVs.
In Aim 2 we will explore the role of TRIM34 as a broadly acting antiviral gene in primates as well as the potential role of TRIM34 in contributing to limiting the evolution of HIV-1 infections within the host.
In Aim 3 we will perform a whole-genome HIV-CRISPR screening approach to find the Interferon-Stimulated Genes (ISGs) that inhibit HIV-1 capsid mutants. In addition to defining a novel HIV restriction by TRIM34 in human cells, this work has the potential to discover novel host antiviral genes that limit SIV and HIV strains from replicating in human cells. Follow-up studies will be focused on furthering our understanding the mechanism of action of genes of interest as well as mechanisms of viral antagonism or escape. Ultimately, manipulation of these factors could be important for approaches aimed at achieving a functional HIV cure.

Public Health Relevance

Eradication of HIV infection and disease remains a significant obstacle in biomedical research. Here we will further our basic understanding of the adaptation of primate lentiviruses to humans and the mechanisms by which human cells block infection. We foresee that defining host genetic barriers to cross-species transmission and intra-host evolution of lentiviruses will have implications for efforts at achieving a functional HIV cure and for improved HIV therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI147877-01
Application #
9846779
Study Section
HIV Molecular Virology, Cell Biology, and Drug Development Study Section (HVCD)
Program Officer
Refsland, Eric William
Project Start
2019-06-14
Project End
2024-05-31
Budget Start
2019-06-14
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109