A Cure for HIV Infection: “Not in My Lifetime” or “Just Around the Corner”?

Michael M. Lederman, Paula M. Cannon, Judith S. Currier, Carl H. June, Hans-Peter Kiem, Daniel R. Kuritzkes, Sharon R. Lewin, David M. Margolis, Joseph M. McCune, John W. Mellors, Timothy W. Schacker, Rafick P. Sekaly, Pablo Tebas, Bruce D. Walker, Daniel C. Douek

Abstract


With the advent and stunning success of combination antiretroviral therapy (ART) to prolong and improve quality of life for persons with HIV infection, HIV research has been afforded the opportunity to pivot towards studies aimed at finding “a cure.” The mere idea that cure of HIV might be possible has energized researchers and the community towards achieving this goal. Funding agencies, both governmental and private, have targeted HIV cure as a high priority; many in the field have responded to these initiatives and the cure research agenda is robust.

In this “salon” two editors of Pathogens and Immunity, Michael Lederman and Daniel Douek ask whether curing HIV is a realistic, scalable objective. We start with an overview perspective and have asked a number of prominent HIV researchers to add to the discussion.


Keywords


HIV; reservoir; eradication; cure; CCR5; functional cure; latency; elite controller; Berlin Patient; inflammation; procoagulant

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References


1. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, Schneider T, Hofmann J, Kucherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692-8. PubMed PMID: 19213682. doi: 10.1056/NEJMoa0802905

2. Hutter G. More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation. N Engl J Med. 2014;371(25):2437-8. PubMed PMID: 25517721. doi: 10.1056/NEJMc1412279#SA1

3. Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101(7):2711-20. PubMed PMID: 12433688. doi: 10.1182/blood-2002-07-2103

4. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350-4. PubMed PMID: 16921384. doi: 10.1038/nature05115

5. Fletcher CV, Staskus K, Wietgrefe SW, Rothenberger M, Reilly C, Chipman JG, Beilman GJ, Khoruts A, Thorkelson A, Schmidt TE, Anderson J, Perkey K, Stevenson M, Perelson AS, Douek DC, Haase AT, Schacker TW. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A. 2014;111(6):2307-12. PubMed PMID: 24469825. Pubmed Central PMCID: PMC3926074. doi: 10.1073/pnas.1318249111

6. Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, Gallien S, Lin NH, Giguel FF, Lavoie L, Ho VT, Armand P, Soiffer RJ, Sagar M, Lacasce AS, Kuritzkes DR. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013;207(11):1694-702. PubMed PMID: 23460751. Pubmed Central PMCID: PMC3636784. doi: 10.1093/infdis/jit086

7. Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, Hunt PW, Hoh R, Stramer SL, Linnen JM, McCune JM, Martin JN, Busch MP, Deeks SG. Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol. 2009;83(1):329-35. PubMed PMID: 18945778. Pubmed Central PMCID: PMC2612329. doi: 10.1128/jvi.01763-08

8. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A, Baker B, Trocha A, Rosenberg R, Mackey E, Ueda P, Lu Z, Cohen D, Wrin T, Petropoulos CJ, Rosenberg ES, Walker BD. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis. 2008;197(4):563-71. PubMed PMID: 18275276. doi: 10.1086/526786

9. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211. PubMed PMID: 23516360. Pubmed Central PMCID: PMC3597518. doi: 10.1371/journal.ppat.1003211

10. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, Hsue P, Emu B, Krone M, Lampiris H, Douek D, Martin JN, Deeks SG. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197(1):126-33. PubMed PMID: 18171295. Pubmed Central PMCID: PMC3466592. doi: 10.1086/524143

11. Sauce D, Larsen M, Fastenackels S, Pauchard M, Ait-Mohand H, Schneider L, Guihot A, Boufassa F, Zaunders J, Iguertsira M, Bailey M, Gorochov G, Duvivier C, Carcelain G, Kelleher AD, Simon A, Meyer L, Costagliola D, Deeks SG, Lambotte O, Autran B, Hunt PW, Katlama C, Appay V. HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood. 2011;117(19):5142-51. PubMed PMID: 21436070. Pubmed Central PMCID: PMC3109539. doi: 10.1182/blood-2011-01-331306

12. Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901-10. PubMed PMID: 24597865. Pubmed Central PMCID: PMC4084652. doi: 10.1056/NEJMoa1300662

13. Henrich TJ, Hanhauser E, Hu Z, Stellbrink HJ, Noah C, Martin JN, Deeks SG, Kuritzkes DR, Pereyra F. Viremic control and viral coreceptor usage in two HIV-1-infected persons homozygous for CCR5 Delta32. AIDS. 2015;29(8):867-76. PubMed PMID: 25730507. Pubmed Central PMCID: PMC4473772. doi: 10.1097/qad.0000000000000629

14. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, Plants J, Seth A, Wilson CC, Deeks SG, Lederman MM, Landay AL. Soluble markers of inflammation and coagulation, but not T-cell activation, are predictors of non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014. PubMed PMID: 24795473. doi: 10.1093/infdis/jiu254

15. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, Ferre AL, Hayes TL, Somsouk M, Hsue PY, Van Natta ML, Meinert CL, Lederman MM, Hatano H, Jain V, Huang Y, Hecht FM, Martin JN, McCune JM, Moreno S, Deeks SG. HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality. PLoS Pathog. 2014;10(5):e1004078. PubMed PMID: 24831517. Pubmed Central PMCID: 4022662. doi: 10.1371/journal.ppat.1004078

16. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, Gripshover B, Salata RA, Taege A, Lisgaris M, McComsey GA, Kirchner E, Baum J, Shive C, Asaad R, Kalayjian RC, Sieg SF, Rodriguez B. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217-26. PubMed PMID: 21917895. Pubmed Central PMCID: 3218674. doi: 10.1093/infdis/jir507

17. Schacker TW, Reilly C, Beilman GJ, Taylor J, Skarda D, Krason D, Larson M, Haase AT. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS. 2005;19(18):2169-71. PubMed PMID: 16284469.

18. Shive CL, Mudd JC, Funderburg NT, Sieg SF, Kyi B, Bazdar DA, Mangioni D, Gori A, Jacobson JM, Brooks AD, Hardacre J, Ammori J, Estes JD, Schacker TW, Rodriguez B, Lederman MM. Inflammatory Cytokines Drive CD4+ T-Cell Cycling and Impaired Responsiveness to Interleukin 7: Implications for Immune Failure in HIV Disease. J Infect Dis. 2014. PubMed PMID: 24585897. doi: 10.1093/infdis/jiu125

19. Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, Robinson J, Huang Y, Epling L, Martin JN, Deeks SG, Meinert CL, Van Natta M, Jabs DA, Lederman MM. Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection. J Infect Dis. 2014. PubMed PMID: 24755434. doi: 10.1093/infdis/jiu238

20. May MT, Gompels M, Delpech V, Porter K, Orkin C, Kegg S, Hay P, Johnson M, Palfreeman A, Gilson R, Chadwick D, Martin F, Hill T, Walsh J, Post F, Fisher M, Ainsworth J, Jose S, Leen C, Nelson M, Anderson J, Sabin C. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS. 2014;28(8):1193-202. PubMed PMID: 24556869. Pubmed Central PMCID: PMC4004637. doi: 10.1097/qad.0000000000000243


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