Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes

Dionysios C Watson, Eirini Moysi, Antonio Valentin, Cristina Bergamaschi, Santhi Devasundaram, Sotirios P Fortis, Jenifer Bear, Elena Chertova, Julian Bess Jr, Ray Sowder, David J Venzon, Claire Deleage, Jacob D Estes, Jeffrey D Lifson, Constantinos Petrovas, Barbara K Felber, George N Pavlakis, Dionysios C Watson, Eirini Moysi, Antonio Valentin, Cristina Bergamaschi, Santhi Devasundaram, Sotirios P Fortis, Jenifer Bear, Elena Chertova, Julian Bess Jr, Ray Sowder, David J Venzon, Claire Deleage, Jacob D Estes, Jeffrey D Lifson, Constantinos Petrovas, Barbara K Felber, George N Pavlakis

Abstract

B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8+ T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (TFH) cells. We studied the effects of native heterodimeric IL-15 (hetIL-15) treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8+ T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8+ cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo-cytometry) of LN revealed increased numbers of granzyme B+ T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals.

Trial registration: ClinicalTrials.gov NCT02452268.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: GNP, CB, AV and BKF are inventors on US Government-owned patents. All other authors declare that they have no competing interests.

Figures

Fig 1. Lymphocyte changes in LN after…
Fig 1. Lymphocyte changes in LN after hetIL-15 treatment.
(A) Step-dose regimen of six SC hetIL-15 administrations in rhesus macaques. LN, blood and mucosal tissue lymphocytes were analyzed before (pre) and after treatment (+hetIL-15). Flow cytometry dot plots of LN mononuclear cells show (B) the frequency of CD8+ memory subsets, naïve (TN, CD28+CD95low), central memory (TCM, CD28highCD95+) and effector memory (TEM, CD28-CD95+), and (D) granzyme B content and cycling status (GrzB+Ki67+) from a representative uninfected macaque (R921) upon hetIL-15 treatment. Graphs (C, E, F) summarize results of 16 macaques treated with hetIL-15 of (C) frequency of effector memory CD8+ T cells, (E) CD8+GrzB+ T cells, and (F) cycling (Ki67+) CD8+ T cells. Analysis was performed on LN of 9 uninfected animals (filled symbols) and 7 SHIV+ macaques (open symbols). Black symbols, pre; red symbols, +hetIL-15. P values are from paired Wilcoxon signed rank test. The 12 animals that were also analyzed for hetIL-15 effects in blood and mucosal tissues (Figs 2 and 3) are indicated by *.
Fig 2. hetIL-15 effects in lymphocytes in…
Fig 2. hetIL-15 effects in lymphocytes in peripheral blood.
(A) Changes in lymphocyte populations were analyzed in blood samples collected from 12 macaques before (black symbols) and after hetIL-15 administration (red symbols). The animals included are indicated by * in Fig 1C and represent 12 of the 16 animals shown in Fig 1. The effects of hetIL-15 treatment on (A) CD8+ Ki67+ T lymphocytes; (B) frequency of CD8+ subsets; (C) CD4+ Ki67+ T lymphocytes; (D) frequency of CD4+ subsets. (E) Effect of hetIL-15 on the blood CD4/CD8 ratio. (F) Effects of hetIL-15 on the granzyme B content of CD4 and CD8 cells in blood. (G-H) NK (CD3-CD16+GrzB-/+) cells were analyzed by measuring cycling status (Ki67 expression; G) and frequency (H). p values are from paired Wilcoxon signed rank test.
Fig 3. hetIL-15 effects in mucosal effector…
Fig 3. hetIL-15 effects in mucosal effector sites.
Analysis of the hetIL-15 effects on lymphocytes from mucosal sites, collected from the same animals shown in Figs 1 and 2. Rectal (N = 12) and vaginal (N = 10) biopsies were obtained before and after hetIL-15 treatment. The mucosal samples were analyzed for changes in Ki67 expression on T cell subsets. The plots show Ki67 levels on TCM (CD95+CD28high), TEM (CD95+CD28low) and CD8+ T cells expressing the γδ TCR (left panels) and CD4+ TCM and TEM (right panels) in rectal (N = 12) (A) and vaginal (B) (from the 10 female macaques) samples collected before (black symbols) and after hetIL-15 treatment (red symbols). p values are from paired Wilcoxon signed rank test.
Fig 4. Accumulation of Ki67 + and…
Fig 4. Accumulation of Ki67+ and GrzB+CD8+ T cells in follicular areas upon hetIL-15 treatment.
(A) Representative confocal images showing the distribution of CD20 (blue), CD3 (red), Ki67 (yellow) and GrzB (cyan) positive cells in peripheral LN from an uninfected macaque (R902) before and after hetIL-15 treatment. Pre-treatment is shown in the upper panels and +hetIL-15 in lower panels throughout. Follicles are defined as CD20hi-dim areas. (B) Higher magnifications from the same LN in panel A of areas indicated by squares. CD20 (blue), CD3 (cyan), CD4 (red) and GrzB (yellow). Follicular areas defined by CD20 (left panel) show increased presence of CD8+ cells (defined as CD3+CD4-) (middle panel) and GrzB+ cells (right panel) upon hetIL-15 treatment. (C) Higher magnification (from panel B) shows presence of CD3+ CD4- GrzB+ (GrzB+CD8+) cells upon hetIL-15 treatment (white arrowheads). (D) Confocal images showing the distribution of CD20 (blue), Ki67 (purple), CD3 (red) and GrzB (yellow) positive cells in a representative follicle. Pre (upper panels) and +hetIL-15 (lower panels) from an SHIV+ macaque (5787). (E) Individual follicles were analyzed upon hetIL-15 treatment in LN from 4 uninfected (3 animals pre and +hetIl-15; one animal +hetIL-15) and 6 SHIV+ macaques (3 animals pre and +hetIl-15; 3 animals +hetIl-15). A range of 2 to 14 follicles were analyzed per animal. The numbers of CD3+CD4-GrzB+ cells per mm2 of area are in individual follicles for each animal are shown. Values of 0 were entered as 1 for the graph display only. Bars indicate average values. p values are calculated by two-way ANOVA for the SHIV+ versus uninfected and pre- versus post-hetIL-15 effects, with random effects to account for the clustered values by animal.
Fig 5. Effects of hetIL-15 on SIV-specific…
Fig 5. Effects of hetIL-15 on SIV-specific CD8+ T cells in peripheral blood and LN of two gag DNA vaccinated MamuA*01+ macaques.
(A) Dot plots showing changes in the frequency of Gag CM9-specific CD8+ T cells in axillary LN and PBMC upon hetIL-15 treatment of macaques P082 and P090. These animals received a SIV gag DNA vaccine. The CM9-tetramer responses are expressed as % of total T cells. For staining, the PE-conjugated CM9 tetramer (MBL International Corporation) was added to the samples 5 min prior to the addition of the antibody cocktail for surface staining. (B, C, D) Histogram overlays show increased levels of Ki67 (B), GrzB (C) and perforin (D) in Gag CM9-specific T cells upon hetIL-15 treatment in LN and PBMC. pre, blue line, +hetIL-15, red line. Numbers within the histogram overlays show the mean fluorescent intensity (MFI) for the specific markers.
Fig 6. Functional assays for CM9-induced SIV-specific…
Fig 6. Functional assays for CM9-induced SIV-specific responses.
Dot plots show production of IFN-γ (A) and degranulation CD107 (B) by CD8+ T cells specific for the MamuA01 restricted Gag CM9 epitope upon specific stimulation of the TCR with the CM9 peptide. The plots show the functional responses at 0 and 3 hours by lymphocytes from LNMC and PBMC of macaque P082. Similar data were obtained from macaque P090. (C) Time course showing the frequency of IFN-γ, TNFα and CD107 positive CD8+ CM9+ T cells in blood, as well as changes in their content of granzyme B and perforin after stimulation with the CM9 peptide in lymphocytes recovered before (black symbols) and after (red symbols) in vivo hetIL-15 treatment. Results in (C) are from a separate experiment with similar results to that shown in panels A and B. (D) Graph showing the frequency of bone marrow cells (macaque P090) loaded with the CM9 peptide or a peptide pool covering HIV-1 Vif undergoing apoptosis (measured as caspase 3 and 7+ cells) after incubation with LNMC obtained before and after hetIL-15 treatment.
Fig 7. hetIL-15 treatment reduces the viral…
Fig 7. hetIL-15 treatment reduces the viral burden.
(A) Quantitation of cell-associated viral RNA in axillary and inguinal LN and PBMC of 4 SHIV+ macaques (T416, T422, R591, T605) upon hetIL-15 treatment. The viral RNA determinations in T416 and T422 are from duplicate measurements from purified flash-frozen LNMC and PBMC. The viral RNA determinations in R591 and T605 are from single measurements of flash-frozen LN before treatment and from two independent flash-frozen LN collected after hetIL-15. Dotted and solid lines denote the two independent LN samples. No inguinal LN was available for T605 post treatment. Axillary LN (blue square), inguinal LN (red triangle) and PBMC (green triangle) data are shown. (B) Quantitation of viral DNA copies from the samples of the macaques in panel A. (C) RNA/DNA ratio of the measurements shown in panels A and B. T416, filled diamond; R591, open diamond; T422, filled circle; T605, open circle. RNA/DNA ratio are for inguinal LN (red symbols) and axillary LN (blue symbols). p value for the difference before and after treatment determined by Mann-Whitney test.

References

    1. Berard M, Brandt K, Bulfone-Paus S, Tough DF. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells. J Immunol. 2003;170(10):5018–26. Epub 2003/05/08. .
    1. Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, et al. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994;180(4):1395–403. Epub 1994/10/01. .
    1. Ma A, Koka R, Burkett P. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol. 2006;24:657–79. Epub 2006/03/23. doi: .
    1. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002;195(12):1523–32. Epub 2002/06/19. doi: .
    1. Zhang X, Sun S, Hwang I, Tough DF, Sprent J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity. 1998;8(5):591–9. Epub 1998/06/10. .
    1. Picker LJ, Reed-Inderbitzin EF, Hagen SI, Edgar JB, Hansen SG, Legasse A, et al. IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. The J Clin Invest. 2006;116(6):1514–24. doi: .
    1. DeGottardi MQ, Okoye AA, Vaidya M, Talla A, Konfe AL, Reyes MD, et al. Effect of Anti-IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques. J Immunol. 2016;197(4):1183–98. doi: .
    1. Colpitts SL, Stoklasek TA, Plumlee CR, Obar JJ, Guo C, Lefrancois L. Cutting edge: the role of IFN-alpha receptor and MyD88 signaling in induction of IL-15 expression in vivo. J Immunol. 2012;188(6):2483–7. doi: .
    1. Colpitts SL, Stonier SW, Stoklasek TA, Root SH, Aguila HL, Schluns KS, et al. Transcriptional regulation of IL-15 expression during hematopoiesis. J Immunol. 2013;191(6):3017–24. doi: .
    1. Cui G, Hara T, Simmons S, Wagatsuma K, Abe A, Miyachi H, et al. Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo. Proc Natl Acad Sci U S A. 2014;111(5):1915–20. doi: .
    1. Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer. J Clin Oncol. 2014. doi: .
    1. Burkett PR, Koka R, Chien M, Chai S, Boone DL, Ma A. Coordinate expression and trans presentation of interleukin (IL)-15Ralpha and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis. J Exp Med. 2004;200(7):825–34. doi: .
    1. Koka R, Burkett PR, Chien M, Chai S, Chan F, Lodolce JP, et al. Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice. J Exp Med. 2003;197(8):977–84. doi: .
    1. Schluns KS, Klonowski KD, Lefrancois L. Transregulation of memory CD8 T-cell proliferation by IL-15Ralpha+ bone marrow-derived cells. Blood. 2004;103(3):988–94. doi: .
    1. Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity. 2002;17(5):537–47. .
    1. Mortier E, Woo T, Advincula R, Gozalo S, Ma A. IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation. J Exp Med. 2008;205(5):1213–25. Epub 2008/05/07. doi: .
    1. Sandau MM, Schluns KS, Lefrancois L, Jameson SC. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15R alpha by the same cells. J Immunol. 2004;173(11):6537–41. .
    1. Bergamaschi C, Rosati M, Jalah R, Valentin A, Kulkarni V, Alicea C, et al. Intracellular Interaction of Interleukin-15 with Its Receptor {alpha} during Production Leads to Mutual Stabilization and Increased Bioactivity. J Biol Chem. 2008;283(7):4189–99. doi: .
    1. Chertova E, Bergamaschi C, Chertov O, Sowder R, Bear J, Roser JD, et al. Characterization and favorable in vivo properties of heterodimeric soluble -15Ralpha cytokine compared to IL-15 monomer. J Biol Chem. 2013;288(25):18093–103. doi: .
    1. Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A. 2006;103(24):9166–71. doi: .
    1. Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol. 2006;177(9):6072–80. .
    1. Bergamaschi C, Jalah R, Kulkarni V, Rosati M, Zhang GM, Alicea C, et al. Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo. J Immunol. 2009;183(5):3064–72. doi: .
    1. Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, et al. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse serum. Blood. 2012;120(1):e1–8. doi: .
    1. Thaysen-Andersen M, Chertova E, Bergamaschi C, Moh ES, Chertov O, Roser J, et al. Recombinant human heterodimeric IL-15 complex displays extensive and reproducible N- and O-linked glycosylation. Glycoconj J. 2015. doi: .
    1. Ng SS, Nagy BA, Jensen SM, Hu X, Alicea C, Fox BA, et al. Heterodimeric IL-15 treatment enhances tumor infiltration, persistence and effector functions of adoptively transferred tumor-specific T cells in the absence of lymphodepletion. Clin Cancer Res. 2016. doi: .
    1. Eberly MD, Kader M, Hassan W, Rogers KA, Zhou J, Mueller YM, et al. Increased IL-15 production is associated with higher susceptibility of memory CD4 T cells to simian immunodeficiency virus during acute infection. J Immunol. 2009;182(3):1439–48. .
    1. Sneller MC, Kopp WC, Engelke KJ, Yovandich JL, Creekmore SP, Waldmann TA, et al. IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8+ T effector memory population in peripheral blood. Blood. 2012;118(26):6845–8. Epub 2011/11/10. doi: .
    1. Waldmann TA, Lugli E, Roederer M, Perera LP, Smedley JV, Macallister RP, et al. Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques. Blood. 2011;117(18):4787–95. doi: .
    1. Lugli E, Goldman CK, Perera LP, Smedley J, Pung R, Yovandich JL, et al. Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. Blood. 2010;116(17):3238–48. doi: .
    1. Lugli E, Mueller YM, Lewis MG, Villinger F, Katsikis PD, Roederer M. IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques. Blood. 2011;118(9):2520–9. doi: .
    1. Berger C, Berger M, Hackman RC, Gough M, Elliott C, Jensen MC, et al. Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood. 2009;114(12):2417–26. doi: .
    1. Mueller YM, Do DH, Altork SR, Artlett CM, Gracely EJ, Katsetos CD, et al. 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. 2008;180(1):350–60. .
    1. Mueller YM, Petrovas C, Bojczuk PM, Dimitriou ID, Beer B, Silvera P, et al. Interleukin-15 increases effector memory CD8+ t cells and NK Cells in simian immunodeficiency virus-infected macaques. J Virol. 2005;79(8):4877–85. doi: .
    1. Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, et al. Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models. Cancer Immunol Res. 2016;4(1):49–60. doi: .
    1. Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, et al. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994;140:105–30. .
    1. Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K, Bae JY, et al. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med. 2015;21(2):132–9. doi: .
    1. Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K, Smith EC, et al. CD4 T follicular helper cell dynamics during SIV infection. The Journal of clinical investigation. 2012;122(9):3281–94. doi: .
    1. Banga R, Procopio FA, Noto A, Pollakis G, Cavassini M, Ohmiti K, et al. PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med. 2016;22(7):754–61. doi: .
    1. Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R, Haddad EK, et al. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med. 2013;210(1):143–56. doi: .
    1. Xu Y, Weatherall C, Bailey M, Alcantara S, De Rose R, Estaquier J, et al. Simian immunodeficiency virus infects follicular helper CD4 T cells in lymphoid tissues during pathogenic infection of pigtail macaques. J Virol. 2013;87(7):3760–73. doi: .
    1. Deleage C, Wietgrefe SW, Del Prete G, Morcock DR, Hao XP, Piatak M Jr, et al. Defining HIV and SIV Reservoirs in Lymphoid Tissues. Pathog Immun. 2016;1(1):68–106. .
    1. Deleage C, Turkbey B, Estes JD. Imaging lymphoid tissues in nonhuman primates to understand SIV pathogenesis and persistence. Curr Opin Virol. 2016;19:77–84. doi: .
    1. Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R. HIV reservoirs: what, where and how to target them. Nat Rev Microbiol. 2016;14(1):55–60. doi: .
    1. Del Prete GQ, Lifson JD, Keele BF. Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies: model parameter considerations and consequences. Curr Opin HIV AIDS. 2016;11(6):546–54. doi: .
    1. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med. 1999;189(6):991–8. Epub 1999/03/17. .
    1. Metzner KJ, Jin X, Lee FV, Gettie A, Bauer DE, Di Mascio M, et al. Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Exp Med. 2000;191(11):1921–31. Epub 2000/06/06. .
    1. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999;283(5403):857–60. Epub 1999/02/05. .
    1. Mueller YM, Do DH, Boyer JD, Kader M, Mattapallil JJ, Lewis MG, et al. CD8+ cell depletion of SHIV89.6P-infected macaques induces CD4+ T cell proliferation that contributes to increased viral loads. J Immunol. 2009;183(8):5006–12. doi: .
    1. Cartwright EK, Spicer L, Smith SA, Lee D, Fast R, Paganini S, et al. CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity. 2016;45(3):656–68. doi: .
    1. Demers KR, Reuter MA, Betts MR. CD8(+) T-cell effector function and transcriptional regulation during HIV pathogenesis. Immunol Rev. 2013;254(1):190–206. doi: .
    1. Nishimura Y, Gautam R, Chun TW, Sadjadpour R, Foulds KE, Shingai M, et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature. 2017;543(7646):559–63. doi: .
    1. Li S, Folkvord JM, Rakasz EG, Abdelaal HM, Wagstaff RK, Kovacs KJ, et al. Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+ Cells In Vivo. J Virol. 2016;90(24):11168–80. doi: .
    1. Connick E, Folkvord JM, Lind KT, Rakasz EG, Miles B, Wilson NA, et al. Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. J Immunol. 2014;193(11):5613–25. doi: .
    1. Connick E, Mattila T, Folkvord JM, Schlichtemeier R, Meditz AL, Ray MG, et al. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol. 2007;178(11):6975–83. .
    1. Petrovas C, Ferrando-Martinez S, Gerner MY, Casazza JP, Pegu A, Deleage C, et al. Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci Trans Med. 2017;9(373). doi: .
    1. Havenar-Daughton C, Lindqvist M, Heit A, Wu JE, Reiss SM, Kendric K, et al. CXCL13 is a plasma biomarker of germinal center activity. Proc Natl Acad Sci U S A. 2016;113(10):2702–7. doi: .
    1. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907–12. doi: .
    1. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–9. doi: .
    1. Villinger F, Miller R, Mori K, Mayne AE, Bostik P, Sundstrom JB, et al. IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques. Vaccine. 2004;22(25–26):3510–21. doi: .
    1. Ansari AA, Mayne AE, Onlamoon N, Pattanapanyasat K, Mori K, Villinger F. Use of recombinant cytokines for optimized induction of antiviral immunity against SIV in the nonhuman primate model of human AIDS. Immunol Res. 2004;29(1–3):1–18. doi: .
    1. Hryniewicz A, Price DA, Moniuszko M, Boasso A, Edghill-Spano Y, West SM, et al. Interleukin-15 but not interleukin-7 abrogates vaccine-induced decrease in virus level in simian immunodeficiency virus mac251-infected macaques. J Immunol. 2007;178(6):3492–504. .
    1. Patel V, Jalah R, Kulkarni V, Valentin A, Rosati M, Alicea C, et al. DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge. Proc Natl Acad Sci U S A. 2013;110(8):2975–80. doi: .
    1. Gerner MY, Kastenmuller W, Ifrim I, Kabat J, Germain RN. Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity. 2012;37(2):364–76. doi: .
    1. Dimopoulos Y, Moysi E, Petrovas C. The Lymph Node in HIV Pathogenesis. Curr HIV/AIDS Rep. 2017. doi: .
    1. Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med. 2016;22(9):1043–9. doi: .
    1. Leong YA, Chen Y, Ong HS, Wu D, Man K, Deleage C, et al. CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles. Nat Immunol. 2016;17(10):1187–96. doi: .
    1. Jones RB, Mueller S, O’Connor R, Rimpel K, Sloan DD, Karel D, et al. A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes. PLoS Patho. 2016;12(4):e1005545 doi: .
    1. Nguyen K, Das B, Dobrowolski C, Karn J. Multiple Histone Lysine Methyltransferases Are Required for the Establishment and Maintenance of HIV-1 Latency. mBio. 2017;8(1). doi: .
    1. Tan RC, Harouse JM, Gettie A, Cheng-Mayer C. In vivo adaptation of SHIV(SF162): chimeric virus expressing a NSI, CCR5-specific envelope protein. J Med Primatol. 1999;28(4–5):164–8. .
    1. Li H, Wang S, Kong R, Ding W, Lee FH, Parker Z, et al. Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A. 2016;113(24):E3413–22. doi: .
    1. Song RJ, Chenine AL, Rasmussen RA, Ruprecht CR, Mirshahidi S, Grisson RD, et al. Molecularly cloned SHIV-1157ipd3N4: a highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade C Env. J Virol. 2006;80(17):8729–38. doi: .
    1. Chang HW, Tartaglia LJ, Whitney JB, Lim SY, Sanisetty S, Lavine CL, et al. Generation and evaluation of clade C simian-human immunodeficiency virus challenge stocks. J Virol. 2015;89(4):1965–74. doi: .
    1. Valentin A, McKinnon K, Li J, Rosati M, Kulkarni V, Pilkington GR, et al. Comparative analysis of SIV-specific cellular immune responses induced by different vaccine platforms in rhesus macaques. Clin Immunol. 2014;155(1):91–107. doi: .
    1. Hansen SG, Piatak M, Ventura AB, Hughes CM, Gilbride RM, Ford JC, et al. Addendum: Immune clearance of highly pathogenic SIV infection. Nature. 2017;547(7661):123–4. doi: .

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