HIV continues to be one of the most prevalent infectious diseases in this world. Our discovery of a novel cellular factor that inhibits the production of HIV by infected cells provides a new target for the development of a novel class of anti-viral drugs and may additionally carry diagnostic and prognostic value. Furthermore, based on the molecular basis of the antiviral activity we hypothesize that other viruses such as Influenza will also be subject to inhibition by huSlfn11.

Public Health Relevance

Compelling evidence indicates that imunological events early after retroviral infection are critical determinants shaping the course of, for instance, HIV/AIDS disease. The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens including retroviruses such as HIV. The innate immune response is not antigen-specific, and is composed of the interferon (IFN) system as wel as cel-based anti-pathogen countermeasures that restrict the replication of pathogens. Understanding the innate immune response and the pathways that promote or restrict the kinetics of different steps of HIV infection is essential for devising nove pharmacological strategies for therapeutic intervention during these infectious disease processes, to develop diagnostic tools or to prevent infection. Significantly more is known about the cellular factors that modulate the early steps in retroviral infection than about those that target the late stages in the viral replication cycle such as those governing virus production (which is also evidenced by the absence of antiviral drugs acting at this point in the viral replication cycle). Interferons exert their antiviral effects through the induction of Interferon Stimulated early response Genes (ISGs). An expanding family of such ISGs are the Schlafen (Slfn) genes, which in addition to IFN are also directly induced by pathogen contact with the cells. In our quest to define the biological function of Slfn proteins we discovered that huSlfn11 potently inhibits the production of retroviruses including HIV. Our studies revealed huSlfn11 expression had no effect on the early steps of the infection cycle, but that huSlfn11 protein acts at the very late stages of replication where new viral proteins are synthesized. A striking hallmark of huSlfn11 function is the selective inhibition of the synthesis of virus-encoded proteins, whereas production host cell proteins are apparently unhindered. The studies proposed in this application aim to determine the specificity of huSlfn11 function, to define and characterize the functional domains of huSlfn11, and to elucidate its mechanism of action in the inhibition of retroviral proteins synthesis inhibition. These molecular processes potentially not only affect HIV replication per se, but might also impact the natural variability of HIV and thus limit the generation of multidrug-resistant HIV strains. The anticipated results will not only shed light onto a novel area of the innate antiviral response against HIV and other retroviruses, but will also provide the necessary understanding of Slfn protein function required to exploit their prospective diagnostic and therapeutic value.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM101982-03S1
Application #
8914843
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sakalian, Michael
Project Start
2012-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$8,424
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093