Reactivation of latent HIV through TLR signaling

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DESCRIPTION (provided by applicant): 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.