The existence of latent reservoirs of HIV-infected cells constitutes the major impediment towards viral eradication. HIV-1 latent reservoirs are small, but extremely long-lived. Latent infection is associated with undetectable levels of viral gene expression and appears to be non-cytopathic. However, upon reactivation, latent viruses enter an active mode of replication in which they are fully competent for spread and induction of disease. The current thinking in the field is that a combination of hypothetical drugs that will reactivate latent viruses (''anti-latency''drugs), with present-day antiretroviral drugs, will be n effective approach toward viral eradication. Pam3C-SK4 is a synthetic triacylated lipopeptide analogue of naturally occurring lipoproteins in gram- negative bacteria, mycobacteria and some gram-positive bacteria;and it is used as a reference compound for TLR-2/1 activation. Using a previously described primary cell model for the study of HIV-1 latency, we have found that the triacylated lipopeptide Pam3C-SK4, but not other TLR agonists tested, is able to induce viral reactivation form latency in central memory CD4 T cells. Our main goal is to understand the signaling pathway activated by Pam3C-SK4 that leads to viral reactivation from latency in CD4 memory T cells. Furthermore, we will study whether Pam3C-SK4 increases the susceptibility to or accelerate the kinetics of apoptosis induction upon virus stimulation, as well as the ability to eliminate or reduce the latent reservoir in vitro. These studies will increase our knowledge on mechanisms of viral reactivation that can be applied to new therapeutic strategies toward HIV-1 eradication.

Public Health Relevance

The existence of latent reservoirs of HIV-infected cells constitutes the major impediment towards viral eradication. The current thinking in the field is that a combination of hypothetical drugs that will reactivate latent viruses (''anti-latency''drug), with present-day antiretroviral drugs, will be an effective approach toward viral eradication. We have found that triacylated lipopeptides are able to induce viral reactivation form latency in central memory CD4 T cells. We propose to characterize how this lipopeptides induced viral reactivation from latency, with the ultimate goal of using this pathway as a target for viral eradication strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI106438-01
Application #
8540681
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Lawrence, Diane M
Project Start
2013-04-16
Project End
2015-03-31
Budget Start
2013-04-16
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$223,750
Indirect Cost
$73,750
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112