The global HIV/AIDS epidemic continues to expand, driven chiefly by sexual transmission of the virus and sharing of contaminated needles among intravenous drug users. The Global Fund and PEPFAR, the two international programs providing the lion's share of antiviral drugs in the developing world, are unable to keep pace with the epidemic. For every 10 subjects placed on antiviral therapy, 16 individuals are newly infected. As the number of infections increases and funds for lifelong treatment become more limited, a serious gap in HIV/AIDS care will inevitably emerge. What can be done to close this gap? Strikingly, the pathogenic challenge posed by lentiviruses, such as HIV-1, has been successfully met in 40+ species of monkeys who have coevolved with their lentiviruses. Surprisingly, the solution is not to suppress the virus, but rather to modify the host response to the virus in a manner that prevents disease. These animals essentially "ignore" their lentivirus, by failing to mount chronic inflammatory and immune activation responses, such as those found in HIV- infected humans. We recently found that the vast majority of CD4 T cells dying in HIV-infected lymphoid tissues are victims of an intensely inflammatory form of programmed cell death termed pyroptosis, which involves caspase-1 activation and inflammasome assembly. Remarkably, this pathway appears to be selectively activated in pathogenic but not non-pathogenic lentiviral infections. We now propose to determine if small-molecule inhibitors of the caspase 1/inflammasome/pyroptosis pathway can block clinical progression to AIDS. Caspase-1 inhibitors are already in clinical trials. If successful, this host-focused strategy could be use as a novel and cost-effective means to prevent disease progression, potentially transforming the care of millions of HIV-infected subjects who are unable to access antiviral therapy. This approach could help realize the dream of an "AIDS-free generation."

Public Health Relevance

Millions of vulnerable HIV-infected individuals in the developing world are at increasing risk of lack of access to lifesaving antiviral medications because of declining global funding for HIV/AIDS and continuing expansion of the epidemic. I am proposing to explore a radically different host-directed strategy that is strongly based on an evolutionary precedent that could preserve CD4 T cell levels, reduce inflammation, and halt progression to AIDS. Specifically, I propose to explore the biological effects of inhibitors of pyroptosis (a form of programmed cell death triggered by abortive HIV infection associated with intense inflammation). If these agents act as I predict, they could provide an urgently needed therapeutic option for HIV-infected individuals throughout the world, including those infected by injecting drug use, who are unable to access antiviral drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1DA036502-02
Application #
8727502
Study Section
Special Emphasis Panel (ZDA1-SXC-E (03))
Program Officer
Purohit, Vishnudutt
Project Start
2013-09-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$955,000
Indirect Cost
$455,000
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Monroe, Kathryn M; Yang, Zhiyuan; Johnson, Jeffrey R et al. (2014) IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343:428-32
Doitsh, Gilad; Galloway, Nicole L K; Geng, Xin et al. (2014) Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505:509-14
Geng, X; Doitsh, G; Yang, Z et al. (2014) Efficient delivery of lentiviral vectors into resting human CD4 T cells. Gene Ther 21:444-9