Publications
Featured Article from the Literature
Evidence for the Cure of HIV Infection by CCR5∆32/∆32 Stem Cell Transplantation
Allers et al, Blood. 2011 Mar 10;117(10):2791-9. Epub 2010 Dec 8.
Abstract
HIV entry into CD4(+) cells requires interaction with a cellular receptor, generally either CCR5 or CXCR4. We have previously reported the case of an HIV-infected patient in whom viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with CCR5Δ32/Δ32 stem cells. However, it was expected that the long-lived viral reservoir would lead to HIV rebound and disease progression during the process of immune reconstitution. In the present study, we demonstrate successful reconstitution of CD4(+) T cells at the systemic level as well as in the gut mucosal immune system after CCR5Δ32/Δ32 stem cell transplantation, while the patient remains without any sign of HIV infection. This was observed although recovered CD4(+) T cells contain a high proportion of activated memory CD4(+) T cells, ie, the preferential targets of HIV, and are susceptible to productive infection with CXCR4-tropic HIV. Furthermore, during the process of immune reconstitution, we found evidence for the replacement of long-lived host tissue cells with donor-derived cells, indicating that the size of the viral reservoir has been reduced over time. In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient.
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Publications from Our Collaboratory
- Viral diagnostics in the era of digital polymerase chain reaction
Sedlak RH and Jerome KR. Diagnostic microbiology and infectious disease. 2013 Jan; 75(1): 1-4. PMID: 23182074 - Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART
Peterson CW, Younan P, Jerome KR, and Kiem HP. Gene therapy. 2013 Jan 31; PMID: 23364313 - Tracking replication-competent HIV reservoirs in infected individuals
Chun TW. Current opinion in HIV and AIDS. 2013 Mar; 8(2): 111-6. PMID: 23380652 - Combinatorial RNA-based gene therapy for the treatment of HIV/AIDS
Chung J, Digiusto DL, and Rossi JJ. Expert opinion on biological therapy. 2013 Mar; 13(3): 437-45. PMID: 23394377 - Functional in vivo delivery of multiplexed anti-HIV-1 siRNAs via a chemically synthesized aptamer with a sticky bridge
Zhou J, Neff CP, Swiderski P, Li H, Smith DD, Aboellail T, Remling-Mulder L, Akkina R, and Rossi JJ. Mol Ther. 2013 Jan; 21(1): 192-200. PMID: 23164935
- Targeted DNA mutagenesis for the cure of chronic viral infections
Schiffer JT, Aubert M, Weber ND, Mintzer E, Stone D, and Jerome KR. J Virol. 2012 Sep; 86(17): 8920-36. PMID: 22718830 - Hematopoietic-stem-cell-based gene therapy for HIV disease
Kiem HP, Jerome KR, Deeks SG, and McCune JM. Cell Stem Cell. 2012 Feb 3; 10(2): 137-47. PMID: 22305563 - Efficient generation, purification, and expansion of CD34(+) hematopoietic progenitor cells from nonhuman primate-induced pluripotent stem cells
Gori JL, Chandrasekaran D, Kowalski JP, Adair JE, Beard BC, D’Souza SL, and Kiem HP. Blood. 2012 Sep 27; 120(13): e35-44. PMID: 22898598 - Extended survival of glioblastoma patients after chemoprotective HSC gene therapy
Adair JE, Beard BC, Trobridge GD, Neff T, Rockhill JK, Silbergeld DL, Mrugala MM, and Kiem HP. Sci Transl Med. 2012 May 9; 4(133): 133ra57. PMID: 22572881 - Novel reporter systems for facile evaluation of I-SceI-mediated genome editing
Munoz NM, Beard BC, Ryu BY, Luche RM, Trobridge GD, Rawlings DJ, Scharenberg AM, and Kiem HP. Nucleic Acids Res. 2012 Jan; 40(2): e14. PMID: 22110042 - Stitching together multiple data dimensions reveals interacting metabolomic and transcriptomic networks that modulate cell regulation
Zhu J, Sova P, Xu Q, Dombek KM, Xu EY, Vu H, Tu Z, Brem RB, Bumgarner RE, and Schadt EE. PLoS biology. 2012 10(4): e1001301. PMID: 22509135 - HIV reservoirs: pathogenesis and obstacles to viral eradication and cure
Chun TW and Fauci AS. Aids. 2012 Jun 19; 26(10): 1261-8. PMID: 22472858 - Optimization and qualification of a multiplex bead array to assess cytokine and chemokine production by vaccine-specific cells
Defawe OD, Fong Y, Vasilyeva E, Pickett M, Carter DK, Gabriel E, Rerks-Ngarm S, Nitayaphan S, Frahm N, McElrath MJ, and De Rosa SC. J Immunol Methods. 2012 Aug 31; 382(1-2): 117-28. PMID: 22626638 - Zinc-finger nuclease editing of human cxcr4 promotes HIV-1 CD4(+) T cell resistance and enrichment
Yuan J, Wang J, Crain K, Fearns C, Kim KA, Hua KL, Gregory PD, Holmes MC, and Torbett BE. Mol Ther. 2012 Apr; 20(4): 849-59. PMID: 22273578 - Simian immunodeficiency virus-induced alterations in monocyte production of tumor necrosis factor alpha contribute to reduced immune activation in sooty mangabeys
Mir KD, Bosinger SE, Gasper M, Ho O, Else JG, Brenchley JM, Kelvin DJ, Silvestri G, Hu SL, and Sodora DL. J Virol. 2012 Jul; 86(14): 7605-15. PMID: 22553338 - Dynamics of envelope evolution in clade C SHIV-infected pig-tailed macaques during disease progression analyzed by ultra-deep pyrosequencing
Tso FY, Tully DC, Gonzalez S, Quince C, Ho O, Polacino P, Ruprecht RM, Hu SL, and Wood C. PLoS One. 2012 7(3): e32827. PMID: 22427893 - Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2
Rolland M, Edlefsen PT, Larsen BB, Tovanabutra S, Sanders-Buell E, Hertz T, deCamp AC, Carrico C, Menis S, Magaret CA, Ahmed H, Juraska M, Chen L, Konopa P, Nariya S, Stoddard JN, Wong K, Zhao H, Deng W, Maust BS, Bose M, Howell S, Bates A, Lazzaro M, O’Sullivan A, Lei E, Bradfield A, Ibitamuno G, Assawadarachai V, O’Connell RJ, deSouza MS, Nitayaphan S, Rerks-Ngarm S, Robb ML, McLellan JS, Georgiev I, Kwong PD, Carlson JM, Michael NL, Schief WR, Gilbert PB, Mullins JI, and Kim JH. Nature. 2012 Oct 18; 490(7420): 417-20. PMID: 22960785 - Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission
Herbeck JT, Muller V, Maust BS, Ledergerber B, Torti C, Di Giambenedetto S, Gras L, Gunthard HF, Jacobson LP, Mullins JI, and Gottlieb GS. Aids. 2012 Jan 14; 26(2): 193-205. PMID: 22089381 - Dissociating markers of senescence and protective ability in memory T cells
Prlic M, Sacks JA, and Bevan MJ. PLoS One. 2012 7(3): e32576. PMID: 22396780 - Creating genetic resistance to HIV
Burnett JC, Zaia JA, and Rossi JJ. Current opinion in immunology. 2012 Oct; 24(5): 625-32. PMID: 22985479 - Coupling endonucleases with DNA end-processing enzymes to drive gene disruption
Certo MT, Gwiazda KS, Kuhar R, Sather B, Curinga G, Mandt T, Brault M, Lambert AR, Baxter SK, Jacoby K, Ryu BY, Kiem HP, Gouble A, Paques F, Rawlings DJ, and Scharenberg AM. Nat Methods. 2012 Oct; 9(10): 973-5. PMID: 22941364 - Engineering domain fusion chimeras from I-OnuI family LAGLIDADG homing endonucleases
Baxter S, Lambert AR, Kuhar R, Jarjour J, Kulshina N, Parmeggiani F, Danaher P, Gano J, Baker D, Stoddard BL, and Scharenberg AM. Nucleic Acids Res. 2012 Sep; 40(16): 7985-8000. PMID: 22684507 - Expanding LAGLIDADG endonuclease scaffold diversity by rapidly surveying evolutionary sequence space
Jacoby K, Metzger M, Shen BW, Certo MT, Jarjour J, Stoddard BL, and Scharenberg AM. Nucleic Acids Res. 2012 Jun; 40(11): 4954-64. PMID: 22334611 - Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia
Ballen KK, Woolfrey AE, Zhu X, Ahn KW, Wirk B, Arora M, George B, Savani BN, Bolwell B, Porter DL, Copelan E, Hale G, Schouten HC, Lewis I, Cahn JY, Halter J, Cortes J, Kalaycio ME, Antin J, Aljurf MD, Carabasi MH, Hamadani M, McCarthy P, Pavletic S, Gupta V, Deeg HJ, Maziarz RT, Horowitz MM, and Saber W. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2012 Sep; 18(9): 1446-54. PMID: 22449610 - Towards an HIV cure: a global scientific strategy
Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Di Mascio M, Katlama C, Lafeuillade A, Landay A, Lederman M, Lewin SR, Maldarelli F, Margolis D, Markowitz M, Martinez-Picado J, Mullins JI, Mellors J, Moreno S, O’Doherty U, Palmer S, Penicaud MC, Peterlin M, Poli G, Routy JP, Rouzioux C, Silvestri G, Stevenson M, Telenti A, Van Lint C, Verdin E, Woolfrey A, Zaia J, and Barre-Sinoussi F. Nat Rev Immunol. 2012 Aug; 12(8): 607-14. PMID: 22814509
- Successful targeting and disruption of an integrated reporter lentivirus using the engineered homing endonuclease Y2 I-AniI
Aubert M, Ryu BY, Banks L, Rawlings DJ, Scharenberg AM, Jerome KR. PLoS One. 2011 Feb 9; 6(2):e16825. PMID: 21399673 - Hematopoietic stem cell expansion and gene therapy
Watts KL, Adair J, Kiem HP. Cytotherapy. 2011 Nov; 13 (10):1164-71. PMID: 21999373 - Differential Effects of HOXB4 and NUP98-HOXA10hd on Hematopoietic Repopulating Cells in a Nonhuman Primate Model
Watts KL, Zhang X, Beard BC, Chiu SY, Trobridge GD, Humphries RK, Kiem HP. Hum Gene Ther. 2011 Sep 6. PMID: 21787196 - Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates
Beard BC, Trobridge GD, Ironside C, McCune JS, Adair JE, Kiem HP. J Clin Invest. 2010 Jul 1;120(7):2345-54. doi: 10.1172/JCI40767. Epub 2010 Jun 14. PMID: 20551514 - Methods for the inference of biological pathways and networks
Bumgarner RE, Yeung KY, 2009. Book chapter in Computational Systems Biology, edited by Jason McDermott, Ram Samudrala, Roger E. Bumgarner, Kristina Montgomery and Renee Ireton. 2009. Methods Mol Biol. 541:225-45. PMID: 19381545 - The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data
Vivian G. Oehler, Ka Yee Yeung, Yongjae E. Choi, Roger E. Bumgarner, Adrian E. Raftery, and Jerald P. Radich, 2009. Blood: 114, 3292-3298. PMCID: PMC2759651 - Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy
Chun TW, Murray D, Justement JS, Hallahan CW, Moir S, Kovacs C, and Fauci AS. The Journal of infectious diseases. 2011 Jul 1; 204(1): 135-8. PMID: 21628667 - HIV-DNA priming alters T cell responses to HIV-adenovirus vaccine even when responses to DNA are undetectable
De Rosa SC, Thomas EP, Bui J, Huang Y, deCamp A, Morgan C, Kalams SA, Tomaras GD, Akondy R, Ahmed R, Lau CY, Graham BS, Nabel GJ, McElrath MJ; National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network. J Immunol. 2011 Sep 15; 187(6):3391-401. Epub 2011 Aug 15. PMID: 21844392 - A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204)
Churchyard GJ, Morgan C, Adams E, Hural J, Graham BS, Moodie Z, Grove D, Gray G, Bekker LG, McElrath MJ, Tomaras GD, Goepfert P, Kalams S, Baden LR, Lally M, Dolin R, Blattner W, Kalichman A, Figueroa JP, Pape J, Schechter M,Defawe O, De Rosa SC, Montefiori DC, Nabel GJ, Corey L, Keefer MC; NIAID HIV Vaccine Trials Network. PLoS One. 2011; 6(8):e21225. Epub 2011 Aug 3. PMID: 21857901 - Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo
Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, Crooks GM, Kohn DB, Gregory PD, Holmes MC, Cannon PM. Nat Biotechnol. 2010 Aug;28(8):839-47. PMID: 20601939 - Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH (2008). Nat Biotechnol. Jul;26(7):808-16. Epub 2008 Jun 29. - Genome editing with engineered zinc finger nucleases
Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Nat Rev Genet. 2010 Sep;11(9):636-46. Review. PMID: 20717154 - Vaccination against heterologous R5 clade C SHIV: prevention of infection and correlates of protection
Lakhashe SK, Wang W, Siddappa NB, Hemashettar G, Polacino P, Hu SL, Villinger F, Else JG, Novembre FJ, Yoon JK, Lee SJ, Montefiori DC, Ruprecht RM, Rasmussen RA. PLoS One. 2011;6(7):e22010. Epub 2011 Jul 20. PMID: 21799765 - Variable prevalence and functional diversity of the antiretroviral restriction factor TRIMCyp in Macaca fascicularis
Dietrich EA, Brennan G, Ferguson B, Wiseman RW, O’Connor D, Hu SL. J Virol. 2011 Oct;85(19):9956-63. Epub 2011 Jul 27. PMID: 21795330 - Comparative immunogenicity of subtype A Human Immunodeficiency Virus type 1 envelope exhibiting differential exposure of conserved neutralization epitopes
Blish CA, Sather DN, Sellhorn G, Stamatatos L, Sun Y, Srivastava I, Barnett SW, Cleveland B, Overbaugh J, Hu SL. J Virol. 2010 Mar;84(5):2573-84. Epub 2009 Dec 16. PMID: 20015987 - Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial
Rolland M, Tovanabutra S, deCamp AC, Frahm N, Gilbert PB, Sanders-Buell E, Heath L, Magaret CA, Bose M, Bradfield A, O’Sullivan A, Crossler J, Jones T, Nau M, Wong K, Zhao H, Raugi DN, Sorensen S, Stoddard JN, Maust BS, Deng W, Hural J, Dubey S, Michael NL, Shiver J, Corey L, Li F, Self SG, Kim J, Buchbinder S, Casimiro DR, Robertson MN, Duerr A, McElrath MJ, McCutchan FE, Mullins JI. Nat Med. 2011 Mar;17(3):366-71. Epub 2011 Feb 27. PMID: 21358627 - Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial
Campbell MS, Mullins JI, Hughes JP, Celum C, Wong KG, Raugi DN, Sorensen S, Stoddard JN, Zhao H, Deng W, Kahle E, Panteleeff D, Baeten JM, McCutchan FE, Albert J, Leitner T, Wald A, Corey L, Lingappa JR; Partners in Prevention HSV/HIV Transmission Study Team. PLoS One. 2011 Mar 2;6(3):e16986. PMID: 21399681 - Cutting edge: β-catenin is dispensable for T cell effector differentiation, memory formation, and recall responses
Prlic M, Bevan MJ. J Immunol. 2011 Aug 15;187(4):1542-6. Epub 2011 Jul 1. PMID: 21724993 - Systemic Administration of Combinatorial dsiRNAs via Nanoparticles Efficiently Suppresses HIV-1 Infection in Humanized Mice
Zhou J, Neff CP, Liu X, Zhang J, Li H, Smith DD, Swiderski P, Aboellail T, Huang Y, Du Q, Liang Z, Peng L, Akkina R, Rossi JJ. Mol Ther. 2011 Sep 27. doi:10.1038/mt.2011.207. PMID: 21952167 - An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice
Neff CP, Zhou J, Remling L, Kuruvilla J, Zhang J, Li H, Smith DD, Swiderski P, Rossi JJ, Akkina R. Sci Transl Med. 2011 Jan 19; 3(66):66ra6. PMID: 21248316 - Tapping natural reservoirs of homing endonucleases for targeted gene modification
Takeuchi R, Lambert AR, Mak AN, Jacoby K, Dickson RJ, Gloor GB, Scharenberg AM, Edgell DR, Stoddard BL. Proc Natl Acad Sci U S A. 2011 Aug 9; 108(32):13077-82. Epub 2011 Jul 22. PMID: 21784983 - Tracking genome engineering outcome at individual DNA breakpoints
Certo MT, Ryu BY, Annis JE, Garibov M, Jarjour J, Rawlings DJ, Scharenberg AM. Nat Methods. 2011 Jul 10;8(8): 671-6. doi:10.1038/nmeth.1648. PMID: 21743461 - HLA-Allele Matched Unrelated Donors Compared to HLA-Matched Sibling Donors: Role of Cell Source and Disease Risk Category
Woolfrey A, Lee SJ, Gooley TA, Malkki M, Martin PJ, Pagel JM, Hansen JA, Petersdorf, E. Bio Blood Marrow Transplant, 16:1382-1387, 2010. NIHMS211026 - HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation
Woolfrey A, Lee SJ, Gooley TA, Malkki M, Martin PJ, Pagel JM, Hansen JA, Petersdorf, E. Bio Blood Marrow Transplant, 16:1382-1387, 2010. NIHMS211026 - Generation of HIV-1 Specific CD8+ Cell Responses Following Allogeneic Hematopoietic Cell Transplant
Woolfrey A, Malhotra U, Harrington R, McNevin J, Manley T, Riddell S, Coombs R, Appelbaum F, Corey L, Storb R. Blood 112: 3484-3487, 2008. PMID: 18698002