?Shock and Kill? has been described as a method to draw out HIV from latently infected cells with latencyreversing drugs and then utilizing the host immune response to eliminate the infected cells. During the last 5-10 years, a wealth of knowledge has been obtained regarding methods of reactivating latent viruses in various systems (i.e., the ?shock? element). Much less has been learned, however, about the ?kill? element of the strategy. This is, in part, because of the very recent realization that viruses reactivating from latency do not necessarily induce cell death, and infected cells are not automatically rendered susceptible to immune killing. NK cells are part of the innate immune system because their effector function is elicited immediately upon recognition of activation ligands on infected cells without prior exposure to the infected cell or viral antigens. In humans, a decreased ability of NK cells to function correlates with increased severity of HSV (6), CMV (12) and hepatitis B virus (3) infections. Using Dr. Barker?s experience with NK cells, and Drs. Planelles?, Margolis? and Karn?s experience with HIV latency, we will begin to explore the events are required, during reactivation from latency, to render cells efficient targets for autologous NK cells. We also propose to understand how autologous NK cells can most effectively be activated so that killing of infected cells is rapid and complete, following reactivation of latent viruses. These experiments were inspired by our recent finding that a TLR1/2 agonist known as Pam3CSK4 can efficiently reactivate HIV-1 from latency in our model of central memory T cells (Planelles et al., manuscript under review), and by observations by others that TLR stimulation can potentiate the activity of natural killer cells. We have also recently shown that latently infected primary memory T-cells are susceptible to NK-killing after proviral reactivation by SAHA (Checkley and Karn;unpublished). After the above pilot experiments have been optimized and results obtained, it is our next objective to perform similar experiments using aviremic patient cells, being exposed to autologous NK cells, in order to assess relevance and feasibility in a relevant ex vivo system.
It has now become clear that reactivation of latent viruses does not always lead to death of the infected cell. Eradicating latent reservoirs of HIV will, therefore, require active clearance of infected cells. Natural killer cells are of great promise because they do not require priming, and can recognize a variety of virus infected cells in a manner that is independent of the viral antigens. We plan to potentiate the activity of NK cells such that they will recognize and kill latently infected cells when they reactivate.
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