USP18 is a significant driver of memory CD4 T-cell reduced viability caused by type I IFN signaling during primary HIV-1 infection

English version

Autoři: Xavier Dagenais-Lussier ^aff001; Hamza Loucif ^aff001; Hugo Cadorel ^aff001; Juliette Blumberger ^aff001; Stéphane Isnard ^aff002; Mariana Gé Bego ^aff003; Éric A. Cohen ^aff003; Jean-Pierre Routy ^aff002; Julien van Grevenynghe ^aff001;
Působiště autorů: Institut national de la recherche scientifique (INRS)-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, QC, Canada ^aff001; Chronic Viral Illness Service and Division of Hematology, McGill University Health Centre, Glen site, Montréal, Québec, Canada ^aff002; Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada ^aff003; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada ^aff004
Vyšlo v časopise: USP18 is a significant driver of memory CD4 T-cell reduced viability caused by type I IFN signaling during primary HIV-1 infection. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008060
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008060

Souhrn

The loss of Memory CD4 T-cells (Mem) is a major hallmark of HIV-1 immuno-pathogenesis and occurs early during the first months of primary infection. A lot of effort has been put into understanding the molecular mechanisms behind this loss, yet they still have not been fully identified. In this study, we unveil the unreported role of USP18 in the deleterious effects of sustained type I IFN signaling on Mem, including HIV-1-specific CD4 T-cells. We find that interfering with IFN-I signaling pathway in infected patients, notably by targeting the interferon-stimulated gene USP18, resulted in reduced PTEN expression similar to those observed in uninfected control donors. We show that AKT activation in response to cytokine treatment, T-cell receptor (TcR) triggering, as well as HIV-1 Gag stimulation was significantly improved in infected patients when PTEN or USP18 were inhibited. Finally, our data demonstrate that higher USP18 in Mem from infected patients prevent proper cell survival and long-lasting maintenance in an AKT-dependent manner. Altogether, we establish a direct role for type I IFN/USP18 signaling in the maintenance of total and virus-specific Mem and provide a new mechanism for the reduced survival of these populations during primary HIV-1 infection.

Klíčová slova:

Apoptosis – Cytokines – Flow cytometry – Genetic interference – HIV-1 – Memory T cells – Small interfering RNAs – T cells

Zdroje

1. Bostik P, Noble ES, Mayne AE, Gargano L, Villinger F, Ansari AA. Central memory CD4 T cells are the predominant cell subset resistant to anergy in SIV disease resistant sooty mangabeys. AIDS. 2006;20(2):181–8. doi: 10.1097/01.aids.0000198092.77948.8a 16511410.

2. Letvin NL, Mascola JR, Sun Y, Gorgone DA, Buzby AP, Xu L, et al. Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys. Science. 2006;312(5779):1530–3. doi: 10.1126/science.1124226 16763152; PubMed Central PMCID: PMC2365913.

3. Mattapallil JJ, Douek DC, Buckler-White A, Montefiori D, Letvin NL, Nabel GJ, et al. Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge. J Exp Med. 2006;203(6):1533–41. doi: 10.1084/jem.20060657 16735692; PubMed Central PMCID: PMC2118314.

4. van Grevenynghe J, Procopio FA, He Z, Chomont N, Riou C, Zhang Y, et al. Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nat Med. 2008;14(3):266–74. doi: 10.1038/nm1728 18311149.

5. van Grevenynghe J, Halwani R, Chomont N, Ancuta P, Peretz Y, Tanel A, et al. Lymph node architecture collapse and consequent modulation of FOXO3a pathway on memory T- and B-cells during HIV infection. Semin Immunol. 2008;20(3):196–203. doi: 10.1016/j.smim.2008.07.008 18757210.

6. Dagenais-Lussier X, Aounallah M, Mehraj V, El-Far M, Tremblay C, Sekaly RP, et al. Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection. J Virol. 2016;90(17):7967–79. doi: 10.1128/JVI.00994-16 27356894; PubMed Central PMCID: PMC4988137.

7. Aounallah M, Dagenais-Lussier X, El-Far M, Mehraj V, Jenabian MA, Routy JP, et al. Current topics in HIV pathogenesis, part 2: Inflammation drives a Warburg-like effect on the metabolism of HIV-infected subjects. Cytokine Growth Factor Rev. 2016;28:1–10. doi: 10.1016/j.cytogfr.2016.01.001 26851985.

8. Dagenais-Lussier X, Mouna A, Routy JP, Tremblay C, Sekaly RP, El-Far M, et al. Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects. Cytokine Growth Factor Rev. 2015;26(6):603–13. doi: 10.1016/j.cytogfr.2015.09.001 26409789.

9. Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 2014;505(7484):509–14. doi: 10.1038/nature12940 24356306; PubMed Central PMCID: PMC4047036.

10. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, et al. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov. 2007;6(12):975–90. doi: 10.1038/nrd2422 18049472.

11. Teijaro JR. Type I interferons in viral control and immune regulation. Curr Opin Virol. 2016;16:31–40. doi: 10.1016/j.coviro.2016.01.001 26812607; PubMed Central PMCID: PMC4821698.

12. Acchioni C, Marsili G, Perrotti E, Remoli AL, Sgarbanti M, Battistini A. Type I IFN—a blunt spear in fighting HIV-1 infection. Cytokine Growth Factor Rev. 2015;26(2):143–58. doi: 10.1016/j.cytogfr.2014.10.004 25466629.

13. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol. 2011;1(6):519–25. doi: 10.1016/j.coviro.2011.10.008 22328912; PubMed Central PMCID: PMC3274382.

14. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472(7344):481–5. doi: 10.1038/nature09907 21478870; PubMed Central PMCID: PMC3409588.

15. Boasso A, Shearer GM. Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol. 2008;126(3):235–42. doi: 10.1016/j.clim.2007.08.015 17916442; PubMed Central PMCID: PMC2275778.

16. d'Ettorre G, Paiardini M, Ceccarelli G, Silvestri G, Vullo V. HIV-associated immune activation: from bench to bedside. AIDS Res Hum Retroviruses. 2011;27(4):355–64. doi: 10.1089/aid.2010.0342 21309730.

17. Hardy GA, Sieg S, Rodriguez B, Anthony D, Asaad R, Jiang W, et al. Interferon-alpha is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers. PLoS One. 2013;8(2):e56527. doi: 10.1371/journal.pone.0056527 23437155; PubMed Central PMCID: PMC3577907.

18. Herbeuval JP, Hardy AW, Boasso A, Anderson SA, Dolan MJ, Dy M, et al. Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci U S A. 2005;102(39):13974–9. doi: 10.1073/pnas.0505251102 16174727; PubMed Central PMCID: PMC1224361.

19. Lehmann C, Harper JM, Taubert D, Hartmann P, Fatkenheuer G, Jung N, et al. Increased interferon alpha expression in circulating plasmacytoid dendritic cells of HIV-1-infected patients. J Acquir Immune Defic Syndr. 2008;48(5):522–30. doi: 10.1097/QAI.0b013e31817f97cf 18645522.

20. von Sydow M, Sonnerborg A, Gaines H, Strannegard O. Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses. 1991;7(4):375–80. doi: 10.1089/aid.1991.7.375 1906289.

21. Boasso A, Hardy AW, Anderson SA, Dolan MJ, Shearer GM. HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation. PLoS One. 2008;3(8):e2961. doi: 10.1371/journal.pone.0002961 18698365; PubMed Central PMCID: PMC2491901.

22. Dagenais-Lussier X, Loucif H, Murira A, Laulhe X, Stager S, Lamarre A, et al. Sustained IFN-I Expression during Established Persistent Viral Infection: A "Bad Seed" for Protective Immunity. Viruses. 2017;10(1). doi: 10.3390/v10010012 29301196; PubMed Central PMCID: PMC5795425.

23. Daugan M, Murira A, Mindt BC, Germain A, Tarrab E, Lapierre P, et al. Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection. Front Immunol. 2016;7:564. doi: 10.3389/fimmu.2016.00564 27994594; PubMed Central PMCID: PMC5136549.

24. Herbeuval JP, Nilsson J, Boasso A, Hardy AW, Kruhlak MJ, Anderson SA, et al. Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci U S A. 2006;103(18):7000–5. doi: 10.1073/pnas.0600363103 16632604; PubMed Central PMCID: PMC1444883.

25. Osokine I, Snell LM, Cunningham CR, Yamada DH, Wilson EB, Elsaesser HJ, et al. Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection. Proc Natl Acad Sci U S A. 2014;111(20):7409–14. doi: 10.1073/pnas.1401662111 24799699; PubMed Central PMCID: PMC4034239.

26. Teijaro JR. Too much of a good thing: Sustained type 1 interferon signaling limits humoral responses to secondary viral infection. Eur J Immunol. 2016;46(2):300–2. doi: 10.1002/eji.201546224 26783074; PubMed Central PMCID: PMC5113021.

27. Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC, Welch M, et al. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science. 2013;340(6129):207–11. doi: 10.1126/science.1235214 23580529; PubMed Central PMCID: PMC3640797.

28. Wilson EB, Brooks DG. Interfering with type I interferon: a novel approach to purge persistent viral infection. Cell Cycle. 2013;12(18):2919–20. doi: 10.4161/cc.26175 23974094; PubMed Central PMCID: PMC3875659.

29. Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J, Cheng G, et al. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science. 2013;340(6129):202–7. doi: 10.1126/science.1235208 23580528; PubMed Central PMCID: PMC3704950.

30. Honke N, Shaabani N, Zhang DE, Hardt C, Lang KS. Multiple functions of USP18. Cell Death Dis. 2016;7(11):e2444. doi: 10.1038/cddis.2016.326 27809302; PubMed Central PMCID: PMC5260889.

31. Basters A, Knobeloch KP, Fritz G. USP18—a multifunctional component in the interferon response. Biosci Rep. 2018;38(6). doi: 10.1042/BSR20180250 30126853; PubMed Central PMCID: PMC6240716.

32. Cheng L, Ma J, Li J, Li D, Li G, Li F, et al. Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J Clin Invest. 2017;127(1):269–79. doi: 10.1172/JCI90745 27941247; PubMed Central PMCID: PMC5199717.

33. Cheng L, Yu H, Li G, Li F, Ma J, Li J, et al. Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection. JCI Insight. 2017;2(12). doi: 10.1172/jci.insight.94366 28614789; PubMed Central PMCID: PMC5470878.

34. Zhen A, Rezek V, Youn C, Lam B, Chang N, Rick J, et al. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J Clin Invest. 2017;127(1):260–8. doi: 10.1172/JCI89488 27941243; PubMed Central PMCID: PMC5199686.

35. Fritsch RD, Shen X, Sims GP, Hathcock KS, Hodes RJ, Lipsky PE. Stepwise differentiation of CD4 memory T cells defined by expression of CCR7 and CD27. J Immunol. 2005;175(10):6489–97. doi: 10.4049/jimmunol.175.10.6489 16272303.

36. Okada R, Kondo T, Matsuki F, Takata H, Takiguchi M. Phenotypic classification of human CD4+ T cell subsets and their differentiation. Int Immunol. 2008;20(9):1189–99. doi: 10.1093/intimm/dxn075 18635582.

37. Molinari F, Frattini M. Functions and Regulation of the PTEN Gene in Colorectal Cancer. Front Oncol. 2013;3:326. doi: 10.3389/fonc.2013.00326 24475377; PubMed Central PMCID: PMC3893597.

38. Jaleco S, Swainson L, Dardalhon V, Burjanadze M, Kinet S, Taylor N. Homeostasis of naive and memory CD4+ T cells: IL-2 and IL-7 differentially regulate the balance between proliferation and Fas-mediated apoptosis. J Immunol. 2003;171(1):61–8. doi: 10.4049/jimmunol.171.1.61 12816983.

39. Riou C, Yassine-Diab B, Van grevenynghe J, Somogyi R, Greller LD, Gagnon D, et al. Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells. J Exp Med. 2007;204(1):79–91. doi: 10.1084/jem.20061681 17190839; PubMed Central PMCID: PMC2118424.

40. Kane LP, Weiss A. The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol Rev. 2003;192:7–20. doi: 10.1034/j.1600-065x.2003.00008.x 12670391.

41. Olagnier D, Sze A, Bel Hadj S, Chiang C, Steel C, Han X, et al. HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. PLoS Pathog. 2014;10(12):e1004575. doi: 10.1371/journal.ppat.1004575 25521510; PubMed Central PMCID: PMC4270795.

42. Yue FY, Kovacs CM, Dimayuga RC, Gu XX, Parks P, Kaul R, et al. Preferential apoptosis of HIV-1-specific CD4+ T cells. J Immunol. 2005;174(4):2196–204. doi: 10.4049/jimmunol.174.4.2196 15699152.

43. Wilson EB, Brooks DG. Decoding the complexity of type I interferon to treat persistent viral infections. Trends Microbiol. 2013;21(12):634–40. doi: 10.1016/j.tim.2013.10.003 24216022; PubMed Central PMCID: PMC3864553.

44. Snell LM, McGaha TL, Brooks DG. Type I Interferon in Chronic Virus Infection and Cancer. Trends Immunol. 2017;38(8):542–57. doi: 10.1016/j.it.2017.05.005 28579323.

45. Mustachio LM, Kawakami M, Lu Y, Rodriguez-Canales J, Mino B, Behrens C, et al. The ISG15-specific protease USP18 regulates stability of PTEN. Oncotarget. 2017;8(1):3–14. doi: 10.18632/oncotarget.13914 27980214; PubMed Central PMCID: PMC5352120.

46. Fraietta JA, Mueller YM, Yang G, Boesteanu AC, Gracias DT, Do DH, et al. Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. PLoS Pathog. 2013;9(10):e1003658. doi: 10.1371/journal.ppat.1003658 24130482; PubMed Central PMCID: PMC3795023.

47. Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C, Dolan MJ, et al. CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood. 2005;106(10):3524–31. doi: 10.1182/blood-2005-03-1243 16046522; PubMed Central PMCID: PMC1895067.

48. Nguyen TP, Bazdar DA, Mudd JC, Lederman MM, Harding CV, Hardy GA, et al. Interferon-alpha inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling. J Leukoc Biol. 2015;97(6):1139–46. doi: 10.1189/jlb.4A0714-345RR 25784743; PubMed Central PMCID: PMC4438745.

49. Honke N, Shaabani N, Merches K, Gassa A, Kraft A, Ehrhardt K, et al. Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN-I responses. Eur J Immunol. 2016;46(2):372–80. doi: 10.1002/eji.201545765 26507703; PubMed Central PMCID: PMC5063111.

50. Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, et al. UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J. 2006;25(11):2358–67. doi: 10.1038/sj.emboj.7601149 16710296; PubMed Central PMCID: PMC1478183.

51. Jiao B, Shi X, Chen Y, Ye H, Yao M, Hong W, et al. Insulin receptor substrate-4 interacts with ubiquitin-specific protease 18 to activate the Jak/STAT signaling pathway. Oncotarget. 2017;8(62):105923–35. doi: 10.18632/oncotarget.22510 29285303; PubMed Central PMCID: PMC5739690.

52. Arimoto KI, Lochte S, Stoner SA, Burkart C, Zhang Y, Miyauchi S, et al. STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nat Struct Mol Biol. 2017;24(3):279–89. doi: 10.1038/nsmb.3378 28165510; PubMed Central PMCID: PMC5365074.

53. Rallon N, Garcia M, Garcia-Samaniego J, Cabello A, Alvarez B, Restrepo C, et al. Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection. PLoS One. 2018;13(3):e0193829. doi: 10.1371/journal.pone.0193829 29518102; PubMed Central PMCID: PMC5843247.

54. Pompura SL, Dominguez-Villar M. The PI3K/AKT signaling pathway in regulatory T-cell development, stability, and function. J Leukoc Biol. 2018. doi: 10.1002/JLB.2MIR0817-349R 29357116.

55. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217–26. doi: 10.1093/infdis/jir507 21917895; PubMed Central PMCID: PMC3218674.

56. Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P, et al. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS. 2010;24(13):1991–2000. doi: 10.1097/QAD.0b013e32833c93ce 20651586.

57. Baker JV, Peng G, Rapkin J, Krason D, Reilly C, Cavert WP, et al. Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases. J Acquir Immune Defic Syndr. 2008;48(5):541–6. doi: 10.1097/QAI.0b013e31817bebb3 18645520; PubMed Central PMCID: PMC3617548.

58. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46(1):72–7. doi: 10.1097/QAI.0b013e318134257a 17621240.

59. Cha L, de Jong E, French MA, Fernandez S. IFN-alpha exerts opposing effects on activation-induced and IL-7-induced proliferation of T cells that may impair homeostatic maintenance of CD4+ T cell numbers in treated HIV infection. J Immunol. 2014;193(5):2178–86. doi: 10.4049/jimmunol.1302536 25063872.

60. Fernandez S, Tanaskovic S, Helbig K, Rajasuriar R, Kramski M, Murray JM, et al. CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells. J Infect Dis. 2011;204(12):1927–35. doi: 10.1093/infdis/jir659 22006994.

61. Younes SA, Talla A, Pereira Ribeiro S, Saidakova EV, Korolevskaya LB, Shmagel KV, et al. Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction. J Clin Invest. 2018;128(11):5083–94. doi: 10.1172/JCI120245 30320604; PubMed Central PMCID: PMC6205369.

62. Biancotto A, Iglehart SJ, Vanpouille C, Condack CE, Lisco A, Ruecker E, et al. HIV-1 induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo. Blood. 2008;111(2):699–704. doi: 10.1182/blood-2007-05-088435 17909079; PubMed Central PMCID: PMC2200839.

63. Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990;9(5):1551–60. 2184033; PubMed Central PMCID: PMC551849.

64. Jenabian MA, El-Far M, Vyboh K, Kema I, Costiniuk CT, Thomas R, et al. Immunosuppressive Tryptophan Catabolism and Gut Mucosal Dysfunction Following Early HIV Infection. J Infect Dis. 2015;212(3):355–66. doi: 10.1093/infdis/jiv037 25616404.

65. Maneglier B, Malleret B, Guillemin GJ, Spreux-Varoquaux O, Devillier P, Rogez-Kreuz C, et al. Modulation of indoleamine-2,3-dioxygenase expression and activity by HIV-1 in human macrophages. Fundam Clin Pharmacol. 2009;23(5):573–81. doi: 10.1111/j.1472-8206.2009.00703.x 19656212.

66. Mellor AL, Lemos H, Huang L. Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now? Front Immunol. 2017;8:1360. doi: 10.3389/fimmu.2017.01360 29163470; PubMed Central PMCID: PMC5663846.

67. Scagnolari C, Monteleone K, Selvaggi C, Pierangeli A, D'Ettorre G, Mezzaroma I, et al. ISG15 expression correlates with HIV-1 viral load and with factors regulating T cell response. Immunobiology. 2016;221(2):282–90. doi: 10.1016/j.imbio.2015.10.007 26563749.

68. Doitsh G, Greene WC. Dissecting How CD4 T Cells Are Lost During HIV Infection. Cell Host Microbe. 2016;19(3):280–91. doi: 10.1016/j.chom.2016.02.012 26962940; PubMed Central PMCID: PMC4835240.

69. Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Sekaly RP. Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS. 2011;6(1):30–6. doi: 10.1097/COH.0b013e3283413775 21242891.

70. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15(8):893–900. doi: 10.1038/nm.1972 19543283; PubMed Central PMCID: PMC2859814.

71. Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK, Boritz E, et al. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature. 2014;511(7511):601–5. doi: 10.1038/nature13554 25043006; PubMed Central PMCID: PMC4418221.

72. van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, Peretz Y, et al. Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis. J Clin Invest. 2011;121(10):3877–88. doi: 10.1172/JCI59211 21926463; PubMed Central PMCID: PMC3195482.