Innate immune activity correlates with CD4 T cell-associated HIV-1 DNA decline during latency-reversing treatment with panobinostat

Journal of Virology

Volumn 89, Issue 20, 2015, Pages 10176-10189

  Olesen, Rikke ^a   Vigano, Selena ^b,c   Rasmussen, Thomas A ^a   Søgaard, Ole S ^a   Ouyang, Zhengyu ^b   Buzon, Maria ^b,c   Bashirova, Arman ^d   Carrington, Mary ^d   Palmer, Sarah ^e   Brinkmann, Christel R ^a   Yu, Xu G ^b,c   Østergaard, Lars ^a   Tolstrup, Martin ^a   Lichterfeld, Mathias ^b,c,f,g  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d FREDERICK NATIONAL LABORATORY FOR CANCER RESEARCH   (United States)

^e UNIVERSITY OF SYDNEY   (Australia)

^f MASSACHUSETTS GENERAL HOSPITAL   (United States)

^g BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD16 ANTIGEN; CD56 ANTIGEN; CD69 ANTIGEN; CYTOKINE; PANOBINOSTAT; VIRUS DNA; HISTONE DEACETYLASE; HISTONE DEACETYLASE INHIBITOR; HYDROXAMIC ACID; IL28B PROTEIN, HUMAN; INDOLE DERIVATIVE; INTERLEUKIN DERIVATIVE; LEUKOCYTE ANTIGEN;

ADAPTIVE IMMUNITY; ARTICLE; CD3+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL LEVEL; CLINICAL EFFECTIVENESS; CONTROLLED STUDY; CYTOKINE RELEASE; DRUG EFFICACY; DRUG RESPONSE; GENE EXPRESSION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; IMMUNE RESPONSE; INNATE IMMUNITY; INTERFERON STIMULATED GENE; NATURAL KILLER CELL; NONHUMAN; PLASMACYTOID DENDRITIC CELL; PREDICTION; PRIORITY JOURNAL; VIRUS GENE; VIRUS LATENCY; ANTAGONISTS AND INHIBITORS; CD8+ T LYMPHOCYTE; CELL COUNT; CLINICAL TRIAL; DENDRITIC CELL; DRUG ADMINISTRATION; DRUG EFFECTS; ENZYMOLOGY; GENETICS; GENOTYPE; GROWTH, DEVELOPMENT AND AGING; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HIV INFECTIONS; IMMUNOLOGY; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; VIROLOGY;

ANTIGENS, CD; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL COUNT; DENDRITIC CELLS; DNA, VIRAL; DRUG ADMINISTRATION SCHEDULE; GENE EXPRESSION; GENOTYPE; HISTONE DEACETYLASE INHIBITORS; HISTONE DEACETYLASES; HIV INFECTIONS; HIV-1; HUMANS; HYDROXAMIC ACIDS; IMMUNITY, INNATE; INDOLES; INTERLEUKINS; KILLER CELLS, NATURAL; VIRUS LATENCY;

EID: 84942154611     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.01484-15     Document Type: Article

References (66)

1. Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F, Chun TW, Chomont N. 2010. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 329:174-180. http://dx.doi.org/10.1126/science.1191047.
2. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. 2009. The challenge of finding a cure for HIV infection. Science 323:1304-1307. http://dx.doi.org/10.1126/science.1165706.
3. Katlama C, Deeks SG, Autran B, Martinez-Picado J, van Lunzen J, Rouzioux C, Miller M, Vella S, Schmitz JE, Ahlers J, Richman DD, Sekaly RP. 2013. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet 38:2109-2117. http://dx.doi.org/10.1016/S0140-6736(13)60104-X.
4. 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, Barre-Sinoussi F. 2012. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 12:607-614. http://dx.doi.org/10.1038/nri3262.
5. 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.
6. 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. 2009. Long-term control of HIV by CCR5 delta32/delta32 stemcell transplantation. N Engl J Med 360:692-698. http://dx.doi.org/10.1056/NEJMoa0802905.
7. Siliciano RF, Greene WC. 2011. HIV latency. Cold Spring Harb Perspect Med 1:a007096. http://dx.doi.org/10.1101/cshperspect.a007096.
8. Ruelas DS, Greene WC. 2013. An integrated overview of HIV-1 latency. Cell 155:519-529. http://dx.doi.org/10.1016/j.cell.2013.09.044.
9. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. 2012. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487:482-485. http://dx.doi.org/10.1038/nature11286.
10. Sogaard O, Graversen M, Leth S, Brinkmann C, Kjaer A, Olesen JE, Denton PW, Nissen S, Sommerfelt M, Rasmussen TA, Ostergaard L, Tolstrup M. 2014. The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays. Abstr XX Int AIDS Conf, Melbourne, NSW, Australia.
11. Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sekaly RP, Lewin SR. 2014. Activation of HIV transcription with short-course vorinostat in HIVinfected patients on suppressive antiretroviral therapy. PLoS Pathog 10: e1004473. http://dx.doi.org/10.1371/journal.ppat.1004473.
12. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, Winckelmann A, Palmer S, Dinarello C, Buzon M, Lichterfeld M, Lewin SR, Østergaard L, Søgaard OS. 2014. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV 1:e13-e21. http://dx.doi.org/10.1016/S2352-3018(14)70014-1.
13. Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, Zhang H, Margolick JB, Blankson JN, Siliciano RF. 2012. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36:491-501. http://dx.doi.org/10.1016/j.immuni.2012.01.014.
14. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, Barre-Sinoussi F, Delfraissy JF, Sinet M, Pancino G, Venet A. 2007. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad SciUSA104:6776-6781. http://dx.doi.org/10.1073/pnas.0611244104.
15. Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, Keele BF, Learn GH, Turnbull EL, Salazar MG, Weinhold KJ, Moore S, CHAVI Clinical Core B, Letvin N, Haynes BF, Cohen MS, Hraber P, Bhattacharya T, Borrow P, Perelson AS, Hahn BH, Shaw GM, Korber BT, McMichael AJ. 2009. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 206:1253-1272. http://dx.doi.org/10.1084/jem.20090365.
16. Northfield JW, Loo CP, Barbour JD, Spotts G, Hecht FM, Klenerman P, Nixon DF, Michaelsson J. 2007. Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T(EMRA) cells in early infection are linked to control of HIV-1 viremia and predict the subsequent viral load set point. J Virol 81:5759-5765. http://dx.doi.org/10.1128/JVI.00045-07.
17. Streeck H, Jolin JS, Qi Y, Yassine-Diab B, Johnson RC, Kwon DS, Addo MM, Brumme C, Routy JP, Little S, Jessen HK, Kelleher AD, Hecht FM, Sekaly RP, Rosenberg ES, Walker BD, Carrington M, Altfeld M. 2009. Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J Virol 83:7641-7648. http://dx.doi.org/10.1128/JVI.00182-09.
18. Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF. 2015. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517:381-385. http://dx.doi.org/10.1038/nature14053.
19. Goulder PJ, Walker BD. 1999. The great escape-AIDS viruses and immune control. Nat Med 5:1233-1235. http://dx.doi.org/10.1038/15184.
20. Jones RB, O'Connor R, Mueller S, Foley M, Szeto GL, Karel D, Lichterfeld M, Kovacs C, Ostrowski MA, Trocha A, Irvine DJ, Walker BD. 2014. Histone deacetylase inhibitors impair the elimination of HIVinfected cells by cytotoxic T-lymphocytes. PLoS Pathog 10:e1004287. http://dx.doi.org/10.1371/journal.ppat.1004287.
21. Barblu L, Machmach K, Gras C, Delfraissy JF, Boufassa F, Leal M, Ruiz-Mateos E, Lambotte O, Herbeuval JP, ANRS EP36 HIV Controllers Study Group. 2012. Plasmacytoid dendritic cells (pDCs) from HIV controllers produce interferon-alpha and differentiate into functional killer pDCs under HIV activation. J Infect Dis 206:790-801. http://dx.doi.org/10.1093/infdis/jis384.
22. 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.
23. Machmach K, Leal M, Gras C, Viciana P, Genebat M, Franco E, Boufassa F, Lambotte O, Herbeuval JP, Ruiz-Mateos E. 2012. Plasmacytoid dendritic cells reduce HIV production in elite controllers. J Virol 86:4245-4252. http://dx.doi.org/10.1128/JVI.07114-11.
24. O'Connell KA, Han Y, Williams TM, Siliciano RF, Blankson JN. 2009. Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. J Virol 83:5028-5034. http://dx.doi.org/10.1128/JVI.02551-08.
25. Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, Colombo S, Brown EE, Shupert WL, Phair J, Goedert JJ, Buchbinder S, Kirk GD, Telenti A, Connors M, O'Brien SJ, Walker BD, Parham P, Deeks SG, McVicar DW, Carrington M. 2007. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 39:733-740. http://dx.doi.org/10.1038/ng2035.
26. Vargas-Inchaustegui DA, Xiao P, Tuero I, Patterson LJ, Robert-Guroff M. 2012. NK and CD4+ T cell cooperative immune responses correlate with control of disease in a macaque simian immunodeficiency virus infection model. J Immunol 189:1878-1885. http://dx.doi.org/10.4049/jimmunol.1201026.
27. Brander C, Goulder P. 2001. The identification of optimal HIVderived CTL epitopes in diverse populations using HIV clade-specific consensus. HIV Sequence Database, Los Alamos National Laboratory, Los Alamos, NM.
28. Lichterfeld M, Yu XG, Cohen D, Addo MM, Malenfant J, Perkins B, Pae E, Johnston MN, Strick D, Allen TM, Rosenberg ES, Korber B, Walker BD, Altfeld M. 2004. HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity. AIDS 18:1383-1392. http://dx.doi.org/10.1097/01.aids.0000131329.51633.a3.
29. Roederer M, Nozzi JL, Nason MC. 2011. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytometry A 79:167-174. http://dx.doi.org/10.1002/cyto.a.21015.
30. Vince N, Bashirova AA, Lied A, Gao X, Dorrell L, McLaren PJ, Fellay J, Carrington M. 2014. HLA class I and KIR genes do not protect against HIV type 1 infection in highly exposed uninfected individuals with hemophilia A. J Infect Dis 210:1047-1051. http://dx.doi.org/10.1093/infdis/jiu214.
31. Cook L, Diem K, Kim W, Scott JD, Jerome KR. 2012. Allele-specific PCR for determination of IL28B genotype. J Clin Microbiol 50:4144-4146. http://dx.doi.org/10.1128/JCM.02084-12.
32. Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, Kinloch S, Cooper D, Schechter M, Tambussi G, Fidler S, Carrington M, Babiker A, Weber J, Koelsch KK, Kelleher AD, Phillips RE, Frater J, SPARTACTrial Investigators. 2014. HIV-1 DNA predicts disease progression and post-treatment virological control. eLife 3:e03821. http://dx.doi.org/10.7554/eLife.03821.
33. Cockerham LR, Deeks SG. 2014. Biomarker reveals HIV's hidden reservoir. eLife 3:e04742. http://dx.doi.org/10.7554/eLife.04742.
34. Kannanganat S, Kapogiannis BG, Ibegbu C, Chennareddi L, Goepfert P, Robinson HL, Lennox J, Amara RR. 2007. Human immunodeficiency virus type 1 controllers but not noncontrollers maintain CD4 T cells coexpressing three cytokines. J Virol 81:12071-12076. http://dx.doi.org/10.1128/JVI.01261-07.
35. West AC, Mattarollo SR, Shortt J, Cluse LA, Christiansen AJ, Smyth MJ, Johnstone RW. 2013. An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res 73: 7265-7276. http://dx.doi.org/10.1158/0008-5472.CAN-13-0890.
36. Nielsen CM, White MJ, Goodier MR, Riley EM. 2013. Functional significance of CD57 expression on human NK cells and relevance to disease. Front Immunol 4:422. http://dx.doi.org/10.3389/fimmu.2013.00422.
37. Moretta A, Poggi A, Pende D, Tripodi G, Orengo AM, Pella N, Augugliaro R, Bottino C, Ciccone E, Moretta L. 1991. CD69-mediated pathway of lymphocyte activation: anti-CD69 monoclonal antibodies trigger the cytolytic activity of different lymphoid effector cells with the exception of cytolytic T lymphocytes expressing T cell receptor alpha/beta. J Exp Med 174:1393-1398. http://dx.doi.org/10.1084/jem.174.6.1393.
38. Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H, Chapman R, Hertzog PJ. 2013. Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res 41:D1040-D1046. http://dx.doi.org/10.1093/nar/gks1215.
39. Urban TJ, Thompson AJ, Bradrick SS, Fellay J, Schuppan D, Cronin KD, Hong L, McKenzie A, Patel K, Shianna KV, McHutchison JG, Goldstein DB, Afdhal N. 2010. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52:1888-1896. http://dx.doi.org/10.1002/hep.23912.
40. Raglow Z, Thoma-Perry C, Gilroy R, Wan YJ. 2013. IL28B genotype and the expression of ISGs in normal liver. Liver Int 33:991-998. http://dx.doi.org/10.1111/liv.12148.
41. Sheahan T, Imanaka N, Marukian S, Dorner M, Liu P, Ploss A, Rice CM. 2014. Interferon lambda alleles predict innate antiviral immune responses and hepatitis C virus permissiveness. Cell Host Microbe 15:190-202. http://dx.doi.org/10.1016/j.chom.2014.01.007.
42. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M. 2009. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461:798-801. http://dx.doi.org/10.1038/nature08463.
43. Golden-Mason L, Bambha KM, Cheng L, Howell CD, Taylor MW, Clark PJ, Afdhal N, Rosen HR. 2011. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C Hepatology 54:1559-1569. http://dx.doi.org/10.1002/hep.24556.
44. Reference deleted.
45. Christiansen AJ, West A, Banks KM, Haynes NM, Teng MW, Smyth MJ, Johnstone RW. 2011. Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies. Proc Natl Acad Sci U S A 108:4141-4146. http://dx.doi.org/10.1073/pnas.1011037108.
46. Lai MD, Chen CS, Yang CR, Yuan SY, Tsai JJ, Tu CF, Wang CC, Yen MC, Lin CC. 2010. An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine. Cancer Gene Ther 17:203-211. http://dx.doi.org/10.1038/cgt.2009.65.
47. Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, Shrikant P, Fenstermaker R, Pili R. 2012. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One 7:e30815. http://dx.doi.org/10.1371/journal.pone.0030815.
48. Liu MK, Hawkins N, Ritchie AJ, Ganusov VV, Whale V, Brackenridge S, Li H, Pavlicek JW, Cai F, Rose-Abrahams M, Treurnicht F, Hraber P, Riou C, Gray C, Ferrari G, Tanner R, Ping LH, Anderson JA, Swanstrom R, CHAVI Core B, Cohen M, Karim SS, Haynes B, Borrow P, Perelson AS, Shaw GM, Hahn BH, Williamson C, Korber BT, Gao F, Self S, McMichael A, Goonetilleke N. 2013. Vertical T cell immunodominance and epitope entropy determine HIV-1 escape. J Clin Invest 123: 380-393. http://dx.doi.org/10.1172/JCI65330.
49. 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.
50. Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, Johnston MN, Cohen D, Robbins GK, Pae E, Alter G, Wurcel A, Stone D, Rosenberg ES, Walker BD, Altfeld M. 2004. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med 200:701-712. http://dx.doi.org/10.1084/jem.20041270.
51. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA. 2006. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107:4781-4789. http://dx.doi.org/10.1182/blood-2005-12-4818.
52. Migueles SA, Weeks KA, Nou E, Berkley AM, Rood JE, Osborne CM, Hallahan CW, Cogliano-Shutta NA, Metcalf JA, McLaughlin M, Kwan R, Mican JM, Davey RT, Jr, Connors M. 2009. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol 83: 11876-11889. http://dx.doi.org/10.1128/JVI.01153-09.
53. Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA. 2002. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417:95-98. http://dx.doi.org/10.1038/417095a.
54. Blankson JN. 2010. Effector mechanisms in HIV-1 infected elite controllers: highly active immune responses? Antiviral Res 85:295-302. http://dx.doi.org/10.1016/j.antiviral.2009.08.007.
55. Ward J, Bonaparte M, Sacks J, Guterman J, Fogli M, Mavilio D, Barker E. 2007. HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood 110:1207-1214. http://dx.doi.org/10.1182/blood-2006-06-028175.
56. Richard J, Sindhu S, Pham TN, Belzile JP, Cohen EA. 2010. HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing. Blood 115:1354-1363. http://dx.doi.org/10.1182/blood-2009-08-237370.
57. 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.
58. Hardy AW, Graham DR, Shearer GM, Herbeuval JP. 2007. HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFNalpha. Proc Natl Acad Sci U S A 104:17453-17458. http://dx.doi.org/10.1073/pnas.0707244104.
59. Reference deleted.
60. Le Bon A, Tough DF. 2002. Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14:432-436. http://dx.doi.org/10.1016/S0952-7915(02)00354-0.
61. Meng Q, Rani MR, Sugalski JM, Judge CJ, Phat S, Rodriguez B, Blanton RE, Anthony DD. 2014. Natural cytotoxicity receptor-dependent natural killer cytolytic activity directed at hepatitis C virus (HCV) is associated with liver inflammation, African American race, IL28B genotype, and response to pegylated interferon/ribavirin therapy in chronic HCV infection. J Infect Dis 209:1591-1601. http://dx.doi.org/10.1093/infdis/jit677.
62. Sun H, Buzon MJ, Shaw A, Berg RK, Yu XG, Ferrando-Martinez S, Leal M, Ruiz-Mateos E, Lichterfeld M. 2014. Hepatitis C therapy with interferon-alpha and ribavirin reduces CD4 T-cell-associated HIV-1 DNA in HIV-1/hepatitis C virus-coinfected patients. J Infect Dis 209:1315-1320. http://dx.doi.org/10.1093/infdis/jit628.
63. Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM, Mounzer K, Tebas P, Jacobson JM, Frank I, Busch MP, Deeks SG, Carrington M, O'Doherty U, Kostman J, Montaner LJ. 2013. Pegylated interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis 207:213-222. http://dx.doi.org/10.1093/infdis/jis663.
64. Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK, Boritz E, Levin D, Wijeyesinghe S, Makamdop KN, del Prete GQ, Hill BJ, Timmer JK, Reiss E, Yarden G, Darko S, Contijoch E, Todd JP, Silvestri G, Nason M, Norgren RB, Jr, Keele BF, Rao S, Langer JA, Lifson JD, Schreiber G, Douek DC. 2014. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511:601-605. http://dx.doi.org/10.1038/nature13554.
65. Schlaepfer E, Audige A, Joller H, Speck RF. 2006. TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J Immunol 176:2888-2895. http://dx.doi.org/10.4049/jimmunol.176.5.2888.
66. Whitney J, Lim S, Osuna C, Sanisetty S, Barnes T, Hraber P, Cihlar T, Geleziunas R, Hesselgesser J. 2015. Treatment with a TLR7 agonist induces transient viremia in SIV-infected ART-suppressed monkeys, abstr 108. Abstr Conf Retrovir Opportunistic Infect, Seattle, WA.