While current antiretroviral (ART) therapies are able to control viral replication, they are unable to fully restore health or a normal immune status. ART-treated individuals still experience several co-morbidities including increased cardiovascular disease, bone disorders and cognitive impairment. Most importantly, therapy interruption leads to the re-emergence of viral replication and AIDS progression. Therefore, the development of new approaches aimed at eradicating or functionally curing HIV infection are desperately needed. Shock- and-kill strategies represent promising approaches to HIV eradication. However, latently infected cells in which viral production has been induced by latency-reversing agents are unlikely to be depleted in the absence of an efficient immune response. An alternative and perhaps more realistic approach to eliminate latently infected cells after viral reactivation relies on the ability of immune cells to mediate antibody-dependent cellular cytotoxicity (ADCC). Through ADCC, effector cells such as NK cells and monocytes can kill infected cells expressing the envelope glycoproteins (Env) through recognition by HIV-specific antibodies. Because the HIV- 1 Vpu and Nef proteins keep Env-CD4 complexes, the major target for ADCC, off the cell surface, this immune mechanism is naturally relatively inefficient. However, we recently discovered that CD4-mimetic compounds (CD4mc) are able to push the HIV-1 envelope glycoproteins (Env) to sample the CD4-bound conformation, resulting in sensitization of HIV-1-infected cells to ADCC. Our observations suggest that CD4mc could be useful for the kill part of the shock-and-kill strategy being pursued to purge the HIV reservoir, and thus could have therapeutic utility in decreasing the size of the viral reservoir upon reactivation. The objective of this proposal is to provide a proof of concept for the value of CD4mc in reducing the size of the viral reservoir in SHIV-infected rhesus macaques, which could expedite application to HIV-1-infected humans.

Public Health Relevance

Persistent reservoirs of cells latently infected by human immunodeficiency virus (HIV-1) potentially can be reactivated to produce virus, creating impediments to HIV-1 eradication or cure. Small CD4-mimetic compounds sensitize virus-expressing cells to antibody-dependent cellular cytotoxicity. The objective of this proposal is to provide a proof of concept for the value of CD4-mimetic compounds in reducing the size of the viral reservoir in a non-human primate model, which could expedite application to HIV-1-infected humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI129017-02
Application #
9432473
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sanders, Brigitte E
Project Start
2017-02-15
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215