Delaney CARE and DARE

Delaney CARE

Delany Care (2)

Research Teams

Research Cores

Activity of Novel Drug Candidates in Primary Cell Models of HIV Latency

Vicente Planelles, Ph.D. – University of Utah, Salt Lake City, Utah
Celsa Spina, Ph.D. – University of California, San Diego

In parallel with the efforts of Project 2.1, Project 2.2 will evaluate various novel experimental compounds in an array of primary CD4+ T cell models of HIV latency. This combined effort will define which in vitro model systems of latency will yield the most predictive results and will provide an expanded platform for testing molecules emerging from an unbiased screen and from basic discovery efforts.

Furthermore, Project 2.2 will ensure a comprehensive approach to the identification of the possible cellular sites of latent HIV infection.  With the development and evaluation of various ex vivo cell models and the analysis of persistent infection in other biologically relevant cell types, such as transitional CD4+ memory cells and macrophages, an extensive and thorough study of HIV latency in vitro will be undertaken.


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Delaney Research Enterprise to Find A Cure

Publications Related to DARE

  1. Hatano H, Delwart E, Norris PJ, Lee T-H, Dunn-Williams J, Hunt P, Hoh R, Stramer SL, Linnen JM, McCune JM, Martin JN, Busch MP, Deeks SG. Evidence for persistent low-level viremia in individuals who control HIV in the absence of antiretroviral therapy, J. Virol. 83:329-35, 2008.
  2. Favre D, Lederer S,* Kanwar B,* Min Ma Z,* Proll S, Kasakow Z, Mold J, Swainson L, Barbour JD, Baskin CR, Palermo R, Pandrea I, Miller C, Katze M, McCune JM. Critical loss of the balance between TH17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathogens, e1000295, Epub Feb 13 2009. (*co-equal authors). PMCID: PMC2635016
  3. Contreras X, Schweneker M, Chen C-S, McCune JM, Deeks S, Martin J, Peterlin BM. Suberoylanilide hydroxamic acid stimulates P-TEFb and reactivates HIV from latently-infected primary cells. J. Biol. Chem, 284:6782, 2009.
  4. Favre D,* Mold J,* Hunt P, Kanwar B, Loke P, Seu L, Barbour J, Lowe MM, Jayawardene A, Aweeka F, Huang Y, Douek D, Brenchley JM, Martin JN, Hecht FM, Deeks SG, McCune JM. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of Th17 and regulatory T cells in HIV disease. Science Translational Medicine, 2:32ra36, 2010. (*co-equal authors) PMCID: PMC3034445
  5. Deeks SG, McCune JM. Can HIV be cured with stem cell therapy? Nature Biotech 28:807-810,2 2010. PMID: 20697404
  6. Hatano H, Hayes T, Dahl V, Sinclair E, Lee T-H, Hoh R, Lampiris H, Hunt P, Palmer S, McCune J, Martin J, Busch M, Shacklett B, Deeks S. A randomized, controlled trial or raltegravir intensification in antiretroviral-treated, HIV-infected patients with suboptimal CD4+ T cell response, J. Infect. Dis. 203:960-8, 2011. PMID: 21402547
  7. Hatano H, Jain V, Hunt PW, Lee T-H, Sinclair E, Do TD, Hoh R, Martin JN, McCune JM, Hecht F, Busch MP, Deeks SG. Cell-based measures of viral persistence are associated with immune activation and PD-1 expressing CD4+ T cells, J Inf Dis, in press, 2012.
  8. Kiem H-P, Jerome K, Deeks SG, McCune JM. Hematopoietic stem cell-based gene therapy for HIV disease. Cell Stem Cell, 10:137-47, 2012.
  9. Cameron PU, Saleh S, Sallmann G, Solomon A, Wightman F, Evans VA, Boucher G, Haddad EK, Sekaly RP, Harman AN, Anderson JL, Jones KL, Mak J, Cunningham AL, Jaworowski A, Lewin SR. Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton. Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16934-9. Epub 2010 Sep 13.
  10. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010 Apr;16(4):452-9. Epub 2010 Mar 7.
  11. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sékaly RP. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009 Aug;15(8):893-900. Epub 2009 Jun 21.
  12. Routy JP, Tremblay CL, Angel JB, Trottier B, Rouleau D, Baril JG, Harris M, Trottier S, Singer J, Chomont N, Sékaly RP, Boulassel MR. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012 May;13(5):291-6. doi: 10.1111/j.1468-1293.2011.00975.x. Epub 2012 Jan 26.
  13. Richman, D.D., Margolis, D.M., DeLaney, M. Greene, W.C, Hazuda, D., Pomerantz, R. (2009). The Challenge of Finding a Cure for HIV Infection. Science. 2009. 323:1304.
  14. Deeks, S. G., B. Autran, B. Berkhout, M. Benkirane, S. Cairns, N. Chomont, T. W. Chun, M. Churchill, M. D. Mascio, C. Katlama, A. Lafeuillade, A. Landay, M. Lederman, S. R. Lewin, F. Maldarelli, D. Margolis, M. Markowitz, J. Martinez‐Picado, J. I. Mullins, J. Mellors, S. Moreno, U. O’Doherty, S. Palmer, M. C. Penicaud, M. Peterlin, G. Poli, J. P. Routy, C. Rouzioux, G. Silvestri, M. Stevenson, A. Telenti, C. V. Lint, E. Verdin, A. Woolfrey, J. Zaia, and F. Barre‐Sinoussi. 2012. Towards an HIV cure: a global scientific strategy. Nature reviews. Immunology 12:607‐614.
  15. Stevenson M. Can HIV be cured? Scientific American. 2008; 299: 78‐83.
  16. Kaushik R, Zhu X, Stranska R, Wu Y, Stevenson M. A cellular restriction dictates the permissivity of non‐dividing monocyte/macrophage to lentivirus and gamma‐retrovirus infection. Cell Host & Microbe. 2009; 6: 68‐80.
  17. Sharkey M, Babic DZ, Greenough T, Gulick R, Kuritzkes DR, Stevenson M. Episomalviral cDNAs identify a reservoir thatfuels viral rebound after treatment interruption and that contributes to treatment failure. PLoS Pathogens. 2011;7(2):e1001303.
  18. Saleh, S., A. Solomon, F. Wightman, M. Xhilaga, P. U. Cameron, and S. R. Lewin. 2007. CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency. Blood 110:4161-4164.
  19. Cameron, P. U., S. Saleh, G. Sallmann, A. Solomon, F. Wightman, V. A. Evans, G. Boucher, E. K. Haddad, R. P. Sekaly, A. N. Harman, J. L. Anderson, K. L. Jones, J. Mak, A. L. Cunningham, A. Jaworowski, and S. R. Lewin. 2010. Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton. Proceedings of the National Academy of Sciences of the United States of America 107:16934-16939.
  20. Wightman, F., A. Solomon, G. Khoury, J. A. Green, L. Gray, P. R. Gorry, Y. S. Ho, N. K. Saksena, J. Hoy, S. M. Crowe, P. U. Cameron, and S. R. Lewin. 2010. Both CD31(+) and CD31(-) naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. The Journal of infectious diseases 202:1738-1748.
  21. Palmer, S., F. Maldarelli, A. Wiegand, B. Bernstein, G. J. Hanna, S. C. Brun, D. J. Kempf, J. Mellors, J. Coffin, and M. King. 2008. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 105: 3879-3884.
  22. Dinoso, J., S. Kim, A. Wiegand, S. Palmer, S. Gange, L. Cranmer, A. O’Shea, M. Callender, A. Spivak, T. Brennan, M. Kearney, M. Proschan, J. Mican , C. Rehm, J. Coffin, J. Mellors, R. Siliciano, and F. Maldarelli. 2009. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci USA 106: 9403-9408.
  23. Bacchetti P, Deeks SG, McCune JM. Breaking free of sample size dogma to perform innovative translational research. Sci Transl Med. 2011 Jun 15; 3(87):87ps24.
  24. Josefsson, L., M.S. King, B. Makitalo, J. Brännström, W. Shao, F. Maldarelli, M.F. Kearney, W. S. Hu, Chen J, Gaines H, Mellors JW, Albert J, Coffin JM, and S. Palmer. 2011. Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A. 108(27):11199-204.
  25. Dahl, V., E. Lee., J. Peterson, S. S. Spudich, I. Leppla, E. Sinclair, D. Fuchs, S. Palmer, R.W. Price. 2011. Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis. 204(12):1936-45.
  26. Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, , Choi ALM, Girling V, Ho t, Li P, Fujimoto K, Lampiris H, Hare CB, Pandori M, Haase AT, Gunthard HF, Fischer M, Shergill A, McQuaid K, Havlir DV, Wong JK. Differences in HIV burden and immune activation within the gut of HIV+ patients on suppressive therapy. Journal of Infectious Diseases. 2010. Nov 15;202(10):1553-61. Epub 2010 Oct 12.
  27. Yukl SA, Shergill A, McQuaid K, Gianella S, Epling L, Girling V, Choi ALM, Li P, Fujimoto K, Downing M, Lampiris H, Li QS, Duan L, Haase A, Hare CB, Sinclair E, Guenthard HF, Fischer M, Wong JK, Havlir DV. Effect of Raltegravir-containing Intensification on HIV Burden and T Cell Activation in Multiple Gut Sites of HIV+ Adults on Suppressive Antiretroviral Therapy. AIDS, 2010. Oct 23;24(16):2451-60.
  28. Vojnov L, Martins MA, Bean AT, Veloso de Santana MG, Sacha JB, Wilson NA, Bonaldo MC, Galler R, Stevenson M,Watkins DI. The Majority of Freshly Sorted Simian Immunodeficiency Virus (SIV)‐Specific CD8+ T Cells Cannot Suppress Viral Replication in SIV‐Infected Macrophages. J Virol. 2012 Apr;86(8):4682‐7.
  29. Smith, M. Z., F. Wightman, and S. R. Lewin. 2012. HIV reservoirs and strategies for eradication. Current HIV/AIDS reports 9:5-15.
  30. Wightman, F., P. Ellenberg, M. Churchill, and S. R. Lewin. 2012. HDAC inhibitors in HIV. Immunology and cell biology 90:47-54.
  31. Josefsson, L., S. Eriksson, E. Sinclair, T. Ho, M. Killian, L. Epling, W. Shao, B. Lewis, P. Bacchetti, L. Loeb, J. Custer, L. Poole, F. M. Hecht and S. Palmer. 2012. Hematopoietic precursor cells isolated from patients on long term suppressive HIV therapy do not contain HIV-1 DNA. J Infect Dis. 206(1):28-34.
  32. Zeng M, Southern PJ, Reilly CS, Beilman GJ, Chipman JG, Schacker TW, Haase AT. Lymphoid tissue damage in HIV‐1 infection depletes naïve T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog. 2012 Jan;8(1):e1002437. Epub 2012 Jan 5. PMID: 22241988.
  33. Zeng M, Paiardini M, Engram JC, Beilman GJ, Chipman JG, Schacker TW, Silvestri G, Haase AT. Critical role for CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution. Blood. 2012 May 21. PMID: 22613799.