In vivo activation of human NK cells by treatment with an interleukin-15 superagonist potently inhibits acute in vivo HIV-1 infection in humanized mice

Journal of Virology

Volumn 89, Issue 12, 2015, Pages 6264-6274

  Seay, Kieran ^a   Church, Candice ^a   Zheng, Jian Hua ^a   Deneroff, Kathryn ^a   Ochsenbauer, Christina ^b   Kappes, John C ^b,c   Liu, Bai ^d   Jeng, Emily K ^d   Wong, Hing C ^d   Goldstein, Harris ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b University of Alabama at Birmingham   (United States)

^c BIRMINGHAM VA MEDICAL CENTER   (United States)

^d ALTOR BIOSCIENCE CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; GRANZYME B; INTERLEUKIN 15 RECEPTOR ALPHA; INTERLEUKIN 15 SUPERAGONIST; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 1; PERFORIN; UNCLASSIFIED DRUG; IL15 PROTEIN, HUMAN; INTERLEUKIN 15;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIGEN EXPRESSION; ARTICLE; BINDING AFFINITY; BINDING SITE; CELL ASSAY; CELL SURFACE; CONTROLLED STUDY; DRUG EFFECT; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESPONSE; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; IMMUNE RESPONSE; IN VITRO STUDY; IN VIVO STUDY; INNATE IMMUNITY; LYMPHOCYTE ACTIVATION; MAXIMUM PLASMA CONCENTRATION; MOLECULAR DYNAMICS; MOUSE; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; ANIMAL; ANTAGONISTS AND INHIBITORS; DISEASE MODEL; HIV INFECTIONS; IMMUNOLOGY; SCID MOUSE;

HUMAN IMMUNODEFICIENCY VIRUS 1; MUS;

ANIMALS; DISEASE MODELS, ANIMAL; HIV INFECTIONS; HUMANS; INTERLEUKIN-15; KILLER CELLS, NATURAL; LYMPHOCYTE ACTIVATION; MICE; MICE, SCID;

EID: 84929587181     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.00563-15     Document Type: Article

References (62)

1. Walker BD, Yu XG. 2013. Unravelling the mechanisms of durable control of HIV-1. Nat Rev Immunol 13:487-498. http://dx.doi.org/10.1038/nri3478.
2. Johnston MI, Fauci AS. 2007. An HIV vaccine-evolving concepts. N Engl J Med 356:2073-2081. http://dx.doi.org/10.1056/NEJMra066267.
3. Mellors JW, Kingsley LA, Rinaldo CR, Jr, Todd JA, Hoo BS, Kokka RP, Gupta P. 1995. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 122:573-579. http://dx.doi.org/10.7326/0003-4819-122-8-199504150-00003.
4. Mellors JW, Rinaldo CR, Jr, Gupta P, White RM, Todd JA, Kingsley LA. 1996. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167-1170. http://dx.doi.org/10.1126/science.272.5265.1167.
5. Lodi S, Meyer L, Kelleher AD, Rosinska M, Ghosn J, Sannes M, Porter K. 2012. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch Intern Med 172:1252-1255. http://dx.doi.org/10.1001/archinternmed.2012.2719.
6. 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. 2013. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. PLoS Pathog 9:e1003211. http://dx.doi.org/10.1371/journal.ppat.1003211.
7. Salgado M, Rabi SA, O'Connell KA, Buckheit RW, III, Bailey JR, Chaudhry AA, Breaud AR, Marzinke MA, Clarke W, Margolick JB, Siliciano RF, Blankson JN. 2011. Prolonged control of replicationcompetent dual-tropic human immunodeficiency virus-1 following cessation of highly active antiretroviral therapy. Retrovirology 8:97. http://dx.doi.org/10.1186/1742-4690-8-97.
8. Alter G, Teigen N, Ahern R, Streeck H, Meier A, Rosenberg ES, Altfeld M. 2007. Evolution of innate and adaptive effector cell functions during acute HIV-1 infection. J Infect Dis 195:1452-1460. http://dx.doi.org/10.1086/513878.
9. Naranbhai V, Altfeld M, Karim SS, Ndung'u T, Karim QA, Carr WH. 2013. Changes in natural killer cell activation and function during primary HIV-1 infection. PLoS One 8:e53251. http://dx.doi.org/10.1371/journal.pone.0053251.
10. Jost S, Altfeld M. 2013. Control of human viral infections by natural killer cells. Annu Rev Immunol 31:163-194. http://dx.doi.org/10.1146/annurev-immunol-032712-100001.
11. Bonaparte MI, Barker E. 2004. Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules. Blood 104:2087-2094. http://dx.doi.org/10.1182/blood-2004-02-0696.
12. Liu K, Catalfamo M, Li Y, Henkart PA, Weng NP. 2002. IL-15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc Natl Acad Sci USA 99:6192-6197. http://dx.doi.org/10.1073/pnas.092675799.
13. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. 2007. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26:503-517. http://dx.doi.org/10.1016/j.immuni.2007.03.006.
14. Mortier E, Woo T, Advincula R, Gozalo S, Ma A. 2008. IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation. J Exp Med 205:1213-1225. http://dx.doi.org/10.1084/jem.20071913
15. Waldmann TA. 2006. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6:595-601. http://dx.doi.org/10.1038/nri1901.
16. Chertova E, Bergamaschi C, Chertov O, Sowder R, Bear J, Roser JD, Beach RK, Lifson JD, Felber BK, Pavlakis GN. 2013. Characterization and favorable in vivo properties of heterodimeric soluble IL-15.IL-15Ralpha cytokine compared to IL-15 monomer. J Biol Chem 288:18093-18103. http://dx.doi.org/10.1074/jbc.M113.461756.
17. Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, Chertova E, Rosenberg SA, Felber BK, Pavlakis GN. 2012. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse serum. Blood 120:e1-e8. http://dx.doi.org/10.1182/blood-2011-10-384362.
18. Wei X, Orchardson M, Gracie JA, Leung BP, Gao B, Guan H, Niedbala W, Paterson GK, McInnes IB, Liew FY. 2001. The Sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. J Immunol 167:277-282. http://dx.doi.org/10.4049/jimmunol.167.1.277.
19. Zhu X, Marcus WD, Xu W, Lee HI, Han K, Egan JO, Yovandich JL, Rhode PR, Wong HC. 2009. Novel human interleukin-15 agonists. J Immunol 183:3598-3607. http://dx.doi.org/10.4049/jimmunol.0901244.
20. Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC, Kong L, Jeng EK, Han K, Marcus WD, Rubinstein MP, Rhode PR, Wong HC. 2013. Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res 73:3075-3086. http://dx.doi.org/10.1158/0008-5472.CAN-12-2357.
21. Edmonds TG, Ding H, Yuan X, Wei Q, Smith KS, Conway JA, Wieczorek L, Brown B, Polonis V, West JT, Montefiori DC, Kappes JC, Ochsenbauer C. 2010. Replication competent molecular clones of HIV-1 expressing Renilla luciferase facilitate the analysis of antibody inhibition in PBMC. Virology 408:1-13. http://dx.doi.org/10.1016/j.virol.2010.08.028.
22. Miyawaki A. 2007. Bringing bioluminescence into the picture. Nat Methods 4:616-617. http://dx.doi.org/10.1038/nmeth0807-616.
23. Han KP, Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, Vyas VV, Marcus WD, Chavaillaz PA, Romero CA, Rhode PR, Wong HC. 2011. IL-15: IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization. Cytokine 56:804-810. http://dx.doi.org/10.1016/j.cyto.2011.09.028.
24. Sango K, Joseph A, Patel M, Osiecki K, Dutta M, Goldstein H. 2010. Highly active antiretroviral therapy potently suppresses HIV infection in humanized Rag2-/-gammac-/-mice. AIDS Res Hum Retroviruses 26: 735-746. http://dx.doi.org/10.1089/aid.2009.0136.
25. Joseph A, Zheng JH, Follenzi A, Dilorenzo T, Sango K, Hyman J, Chen K, Piechocka-Trocha A, Brander C, Hooijberg E, Vignali DA, Walker BD, Goldstein H. 2008. Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. J Virol 82:3078-3089. http://dx.doi.org/10.1128/JVI.01812-07.
26. Seay K, Qi X, Zheng JH, Zhang C, Chen K, Dutta M, Deneroff K, Ochsenbauer C, Kappes JC, Littman DR, Goldstein H. 2013. Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. PLoS One 8:e63537. http://dx.doi.org/10.1371/journal.pone.0063537.
27. Alter G, Malenfant JM, Altfeld M. 2004. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 294:15-22. http://dx.doi.org/10.1016/j.jim.2004.08.008.
28. Zamai L, Mariani AR, Zauli G, Rodella L, Rezzani R, Manzoli FA, Vitale M. 1998. Kinetics of in vitro natural killer activity against K562 cells as detected by flow cytometry. Cytometry 32:280-285. http://dx.doi.org/10.1002/(SICI)1097-0320(19980801)32:4<280::AID-CYTO4>3.0.CO;2-M.
29. Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, Fauci AS. 1989. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci USA 86:2365-2368. http://dx.doi.org/10.1073/pnas.86.7.2365.
30. Zhang T, Li Y, Wang YJ, Wang X, Young M, Douglas SD, Ho WZ. 2007. Natural killer cell inhibits human immunodeficiency virus replication in chronically infected immune cells. Antiviral Res 73:132-139. http://dx.doi.org/10.1016/j.antiviral.2006.08.006.
31. Perdomo MF, Levi M, Sallberg M, Vahlne A. 2008. Neutralization of HIV-1 by redirection of natural antibodies. Proc Natl Acad Sci USA 105:12515-12520. http://dx.doi.org/10.1073/pnas.0805777105.
32. Gomes-Giacoia E, Miyake M, Goodison S, Sriharan A, Zhang G, You L, Egan JO, Rhode PR, Parker AS, Chai KX, Wong HC, Rosser CJ. 2014. Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion. PLoS One 9:e96705. http://dx.doi.org/10.1371/journal.pone.0096705.
33. Leong JW, Fehniger TA. 2011. Human NK cells: SET to kill. Blood 117:2297-2298. http://dx.doi.org/10.1182/blood-2011-01-327247.
34. Kim TD, Lee SU, Yun S, Sun HN, Lee SH, Kim JW, Kim HM, Park SK, Lee CW, Yoon SR, Greenberg PD, Choi I. 2011. Human microRNA-27a* targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity. Blood 118:5476-5486. http://dx.doi.org/10.1182/blood-2011-04-347526.
35. Brown BK, Wieczorek L, Kijak G, Lombardi K, Currier J, Wesberry M, Kappes JC, Ngauy V, Marovich M, Michael N, Ochsenbauer C, Montefiori DC, Polonis VR. 2012. The role of natural killer (NK) cells and NK cell receptor polymorphisms in the assessment of HIV-1 neutralization. PLoS One 7:e29454. http://dx.doi.org/10.1371/journal.pone.0029454.
36. Chenine AL, Wieczorek L, Sanders-Buell E, Wesberry M, Towle T, Pillis DM, Molnar S, McLinden R, Edmonds T, Hirsch I, O'Connell R, McCutchan FE, Montefiori DC, Ochsenbauer C, Kappes JC, Kim JH, Polonis VR, Tovanabutra S. 2013. Impact of HIV-1 backbone on neutralization sensitivity: neutralization profiles of heterologous envelope glycoproteins expressed in native subtype C and CRF01_AE backbone. PLoS One 8:e76104. http://dx.doi.org/10.1371/journal.pone.0076104.
37. deCamp A, Hraber P, Bailer RT, Seaman MS, Ochsenbauer C, Kappes J, Gottardo R, Edlefsen P, Self S, Tang H, Greene K, Gao H, Daniell X, Sarzotti-Kelsoe M, Gorny MK, Zolla-Pazner S, LaBranche CC, Mascola JR, Korber BT, Montefiori DC. 2014. Global panel of HIV-1 Env reference strains for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol 88:2489-2507. http://dx.doi.org/10.1128/JVI.02853-13.
38. McLinden RJ, Labranche CC, Chenine AL, Polonis VR, Eller MA, Wieczorek L, Ochsenbauer C, Kappes JC, Perfetto S, Montefiori DC, Michael NL, Kim JH. 2013. Detection of HIV-1 neutralizing antibodies in a human CD4(+)/CXCR4(+)/CCR5(+) T-lymphoblastoid cell assay system. PLoS One 8:e77756. http://dx.doi.org/10.1371/journal.pone.0077756.
39. Naarding MA, Fernandez N, Kappes JC, Hayes P, Ahmed T, Icyuz M, Edmonds TG, Bergin P, Anzala O, Hanke T, Clark L, Cox JH, Cormier E, Ochsenbauer C, Gilmour J. 2014. Development of a luciferase based viral inhibition assay to evaluate vaccine induced CD8 T-cell responses. J Immunol Methods 409:161-173. http://dx.doi.org/10.1016/j.jim.2013.11.021.
40. Ochsenbauer C, Edmonds TG, Ding H, Keele BF, Decker J, Salazar MG, Salazar-Gonzalez JF, Shattock R, Haynes BF, Shaw GM, Hahn BH, Kappes JC. 2012. Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. J Virol 86:2715-2728. http://dx.doi.org/10.1128/JVI.06157-11.
41. Pace CS, Song R, Ochsenbauer C, Andrews CD, Franco D, Yu J, Oren DA, Seaman MS, Ho DD. 2013. Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1. Proc Natl Acad Sci USA 110:13540-13545. http://dx.doi.org/10.1073/pnas.1304985110.
42. Sarzotti-Kelsoe M, Daniell X, Todd CA, Bilska M, Martelli A, LaBranche C, Perez LG, Ochsenbauer C, Kappes JC, Rountree W, Denny TN, Montefiori DC. 2014. Optimization and validation of a neutralizing antibody assay for HIV-1 in A3R5 cells. J Immunol Methods 409:147-160. http://dx.doi.org/10.1016/j.jim.2014.02.013.
43. Dons'koi BV, Chernyshov VP, Osypchuk DV. 2011. Measurement of NKactivity in whole blood by the CD69 up-regulation after co-incubation with K562, comparison with NK cytotoxicity assays and CD107a degranulation assay. J Immunol Methods 372:187-195. http://dx.doi.org/10.1016/j.jim.2011.07.016.
44. Shah AH, Sowrirajan B, Davis ZB, Ward JP, Campbell EM, Planelles V, Barker E. 2010. Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu. Cell Host Microbe 8:397-409. http://dx.doi.org/10.1016/j.chom.2010.10.008.
45. Soudja SM, Ruiz AL, Marie JC, Lauvau G. 2012. Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 37:549-562. http://dx.doi.org/10.1016/j.immuni.2012.05.029.
46. Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A, Streeck H, Waring M, Meier A, Brander C, Lifson JD, Allen TM, Carrington M, Altfeld M. 2007. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 204:3027-3036. http://dx.doi.org/10.1084/jem.20070695.
47. Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, Trowsdale J, Wilson M, O'Brien SJ, Carrington M. 2002. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 31:429-434. http://dx.doi.org/10.1038/ng934.
48. Chang JJ, Altfeld M. 2010. Innate immune activation in primary HIV-1 infection. J Infect Dis 202(Suppl 2):S297-S301. http://dx.doi.org/10.1086/655657.
49. Cohen GB, Gandhi RT, Davis DM, Mandelboim O, Chen BK, Strominger JL, Baltimore D. 1999. The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIVinfected cells from NK cells. Immunity 10:661-671. http://dx.doi.org/10.1016/S1074-7613(00)80065-5.
50. Chan CJ, Smyth MJ, Martinet L. 2014. Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ 21:5-14. http://dx.doi.org/10.1038/cdd.2013.26.
51. Norman JM, Mashiba M, McNamara LA, Onafuwa-Nuga A, Chiari-Fort E, Shen W, Collins KL. 2011. The antiviral factor APOBEC3G enhances the recognition of HIV-infected primary T cells by natural killer cells. Nat Immunol 12:975-983. http://dx.doi.org/10.1038/ni.2087.
52. d'Ettorre G, Andreotti M, Carnevalini M, Andreoni C, Zaffiri L, Vullo V, Vella S, Mastroianni CM. 2006. Interleukin-15 enhances the secretion of IFN-gamma and CC chemokines by natural killer cells from HIV viremic and aviremic patients. Immunol Lett 103:192-195. http://dx.doi.org/10.1016/j.imlet.2005.10.001.
53. Mueller YM, Katsikis PD. 2010. IL-15 in HIV infection: pathogenic or therapeutic potential? Eur Cytokine Netw 21:219-221. http://dx.doi.org/10.1684/ecn.2010.0198.
54. Mueller YM, Bojczuk PM, Halstead ES, Kim AH, Witek J, Altman JD, Katsikis PD. 2003. IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 101:1024-1029. http://dx.doi.org/10.1182/blood-2002-07-1957.
55. Amicosante M, Poccia F, Gioia C, Montesano C, Topino S, Martini F, Narciso P, Pucillo LP, D'Offizi G. 2003. Levels of interleukin-15 in plasma may predict a favorable outcome of structured treatment interruption in patients with chronic human immunodeficiency virus infection. J Infect Dis 188:661-665. http://dx.doi.org/10.1086/377454.
56. Walter J, Ghosh MK, Kuhn L, Semrau K, Sinkala M, Kankasa C, Thea DM, Aldrovandi GM. 2009. High concentrations of interleukin 15 in breast milk are associated with protection against postnatal HIV transmission. J Infect Dis 200:1498-1502. http://dx.doi.org/10.1086/644603.
57. Eberly MD, Kader M, Hassan W, Rogers KA, Zhou J, Mueller YM, Mattapallil MJ, Piatak M, Jr, Lifson JD, Katsikis PD, Roederer M, Villinger F, Mattapallil JJ. 2009. Increased IL-15 production is associated with higher susceptibility of memory CD4 T cells to simian immunodeficiency virus during acute infection. J Immunol 182:1439-1448. http://dx.doi.org/10.4049/jimmunol.182.3.1439.
58. Mueller YM, Do DH, Altork SR, Artlett CM, Gracely EJ, Katsetos CD, Legido A, Villinger F, Altman JD, Brown CR, Lewis MG, Katsikis PD. 2008. IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses. J Immunol 180:350-360. http://dx.doi.org/10.4049/jimmunol.180.1.350.
59. Steel JC, Waldmann TA, Morris JC. 2012. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci 33:35-41. http://dx.doi.org/10.1016/j.tips.2011.09.004.
60. Epardaud M, Elpek KG, Rubinstein MP, Yonekura AR, Bellemare-Pelletier A, Bronson R, Hamerman JA, Goldrath AW, Turley SJ. 2008. Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res 68:2972-2983. http://dx.doi.org/10.1158/0008-5472.CAN-08-0045.
61. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, Stephenson KE, Chang HW, Shekhar K, Gupta S, Nkolola JP, Seaman MS, Smith KM, Borducchi EN, Cabral C, Smith JY, Blackmore S, Sanisetty S, Perry JR, Beck M, Lewis MG, Rinaldi W, Chakraborty AK, Poignard P, Nussenzweig MC, Burton DR. 2013. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIVinfected rhesus monkeys. Nature 503:224-228. http://dx.doi.org/10.1038/nature12744.
62. Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S, Nogueira L, Eisenreich TR, Liu C, Gazumyan A, Schaefer U, Furze RC, Seaman MS, Prinjha R, Tarakhovsky A, Ravetch JV, Nussenzweig MC. 2014. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989-999. http://dx.doi.org/10.1016/j.cell.2014.07.043.