?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infected primary memory T-cells are susceptible to NK-killing after proviral reactivation by SAHA (Checkley and Karn;unpublished).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.
|Davis, Zachary B; Cogswell, Andrew; Scott, Hamish et al. (2016) A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells. PLoS Pathog 12:e1005421|
|Imaz, Arkaitz; Martinez-Picado, Javier; NiubÃ³, Jordi et al. (2016) HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen. J Infect Dis 214:1512-1519|
|Honeycutt, Jenna B; Wahl, Angela; Baker, Caroline et al. (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest 126:1353-66|
|Tokarev, Andrey; Stoneham, Charlotte; Lewinski, Mary K et al. (2016) Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1. J Virol 90:2486-502|
|Victor Garcia, J (2016) Humanized mice for HIV and AIDS research. Curr Opin Virol 19:56-64|
|Smith, Davey M; Nakazawa, Masato; Freeman, Michael L et al. (2016) Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment. Clin Infect Dis 63:1517-1524|
|Gianella, Sara; Anderson, Christy M; Var, Susanna R et al. (2016) Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection. J Virol 90:3944-52|
|Garcia, J Victor (2016) In vivo platforms for analysis of HIV persistence and eradication. J Clin Invest 126:424-31|
|Lee, Sook-Kyung; Zhou, Shuntai; Baldoni, Pedro L et al. (2016) Quantification of the Latent HIV-1 Reservoir Using Ultra Deep Sequencing and Primer ID In A Viral Outgrowth Assay. J Acquir Immune Defic Syndr :|
|Wagner, Gabriel A; Chaillon, Antoine; Liu, Siqi et al. (2016) HIV-associated neurocognitive disorder is associated with HIV-1 dual infection. AIDS 30:2591-2597|
Showing the most recent 10 out of 187 publications