?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infected primary memory T-cells are susceptible to NK-killing after proviral reactivation by SAHA (Checkley and Karn;unpublished).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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096113-03
Application #
8725368
Study Section
Special Emphasis Panel (ZAI1-JBS-A (M1))
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$29
Indirect Cost
$9,821
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Honeycutt, Jenna B; Sheridan, Patricia A; Matsushima, Glenn K et al. (2015) Humanized mouse models for HIV-1 infection of the CNS. J Neurovirol 21:301-9
King, Helen L; Keller, Samuel B; Giancola, Michael A et al. (2014) Pre-exposure prophylaxis accessibility research and evaluation (PrEPARE Study). AIDS Behav 18:1722-5
Manson McManamy, Mary E; Hakre, Shweta; Verdin, Eric M et al. (2014) Therapy for latent HIV-1 infection: the role of histone deacetylase inhibitors. Antivir Chem Chemother 23:145-9
Spivak, Adam M; Andrade, Adriana; Eisele, Evelyn et al. (2014) A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis 58:883-90
Duverger, Alexandra; Wolschendorf, Frank; Anderson, Joshua C et al. (2014) Kinase control of latent HIV-1 infection: PIM-1 kinase as a major contributor to HIV-1 reactivation. J Virol 88:364-76
Denton, Paul W; Long, Julie M; Wietgrefe, Stephen W et al. (2014) Targeted cytotoxic therapy kills persisting HIV infected cells during ART. PLoS Pathog 10:e1003872
Abreu, Celina M; Price, Sarah L; Shirk, Erin N et al. (2014) Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One 9:e97257
Archin, Nancie M; Margolis, David M (2014) Emerging strategies to deplete the HIV reservoir. Curr Opin Infect Dis 27:29-35
Liu, Pingyang; Xiang, Yanhui; Fujinaga, Koh et al. (2014) Release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein (snRNP) activates hexamethylene bisacetamide-inducible protein (HEXIM1) transcription. J Biol Chem 289:9918-25
Persaud, Deborah; Patel, Kunjal; Karalius, Brad et al. (2014) Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr 168:1138-46

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