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NK Response Correlates with HIV Decrease in Pegylated IFN-Α2a

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NK Response Correlates with HIV Decrease in Pegylated IFN-Α2a Published June 28, 2019, doi:10.4049/jimmunol.1801511 The Journal of Immunology NK Response Correlates with HIV Decrease in Pegylated IFN-a2a–Treated ART-Suppressed Subjects Emmanouil Papasavvas,* Livio Azzoni,* Andrew V. Kossenkov,* Noor Dawany,† Knashawn H. Morales,‡ Matthew Fair,* Brian N. Ross,* Kenneth Lynn,x Agnieszka Mackiewicz,* Karam Mounzer,{ Pablo Tebas,‡ Jeffrey M. Jacobson,‖ Jay R. Kostman,# Louise Showe,* and Luis J. Montaner* We previously reported that pegylated IFN-a2a (Peg–IFN-a2a) added to antiretroviral therapy (ART)–suppressed, HIV-infected subjects resulted in plasma HIV control and integrated HIV DNA decrease. We now evaluated whether innate NK cell activity or PBMC transcriptional profiles were associated with decreases in HIV measures. Human peripheral blood was analyzed prior to Peg–IFN-a2a administration (ART, baseline), after 5 wk of ART+Peg–IFN-a2a, and after 12 wk of Peg–IFN-a2a monotherapy (primary endpoint). After 5 wk of ART+Peg–IFN-a2a, immune subset frequencies were preserved, and induction of IFN- stimulated genes was noted in all subjects except for a subset in which the lack of IFN-stimulated gene induction was associated with increased expression of microRNAs. Viral control during Peg–IFN-a2a monotherapy was associated with 1) higher levels of NK cell activity and IFN-g–induced protein 10 (IP-10) on ART (preimmunotherapy) and 2) downmodulation of NK cell KIR2DL1 and KIR2DL2/DL3 expression, transcriptional enrichment of expression of genes associated with NK cells in HIV controller subjects, and higher ex vivo IFN-a–induced NK cytotoxicity after 5 wk of ART+Peg–IFN-a2a. Integrated HIV DNA decline after immunotherapy was also associated with gene expression patterns indicative of cell-mediated activation and NK cytotoxicity. Overall, an increase in innate activity and NK cell cytotoxicity were identified as correlates of Peg–IFN-a2a–mediated HIV control. The Journal of Immunology, 2019, 203: 000–000. nterferon-a is a type I IFN produced by leukocytes as part of lysis of autologous HIV-infected CD4+ T cell targets ex vivo the host’s TLR-mediated antiviral response (1). Type I IFNs (11, 12), suggesting that IFN-a immunotherapy may activate I modulate cellular antiviral immune responses in vivo either similar mechanisms in vivo to control HIV infection. directly by activation of antiviral host restriction factors (2) or Several human clinical trials in which IFN-a immunotherapy indirectly via stimulation of innate NK cell–mediated responses was administered without antiretroviral therapy (ART) in HIV- by guest on October 1, 2021. Copyright 2019 Pageant Media Ltd. (3–6). Clinical trials with IFN-a support modulation of cell- infected viremic individuals support a predominantly anti-HIV mediated responses as an outcome of immunotherapy, leading to effect without advancement of disease progression (13–23). In increased perforin expression in NK and CD8+ T cells (7, 8), the absence of ART, temporal reductions of HIV plasma viral load increases in CD16+CD56+ NK cell numbers (9), and activation of following administration of pegylated IFN-a2a (Peg–IFN-a2a) CD56+ NK cells (10). Activation of innate host restriction factors were also associated with activation of baseline levels of host and NK responses have been associated with control of HIV and restriction factors, indicating a role for IFN-induced gene induction *The Wistar Institute, Philadelphia, PA 19104; †The Children’s Hospital of Philadelphia, The microarray data presented in this article have been submitted to the Gene ‡ http://classic.jimmunol.org Philadelphia, PA 19104; Perelman School of Medicine, University of Pennsylvania, Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number Philadelphia, PA 19104; xPresbyterian Hospital–University of Pennsylvania Hos- GSE107549. pital, Philadelphia, PA 19104; {Jonathan Lax Immune Disorders Treatment Center, Address correspondence and reprint requests to Dr. Louise Showe and Dr. Luis J. Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA 19107; ‖ Montaner, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. E-mail Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; addresses: [email protected] (L.S.) and [email protected] (L.J.M.) and #John Bell Health Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA 19107 The online version of this article contains supplemental material. ORCIDs: 0000-0002-1536-0418 (A.V.K.); 0000-0003-2983-3893 (N.D.); 0000-0001- Abbreviations used in this article: ADCC, Ab-dependent cytotoxicity; ART, Downloaded from 5345-7942 (P.T.); 0000-0002-7818-4220 (L.S.). antiretroviral therapy; AUC, area under the curve; BD, Becton Dickinson; BDCA1, blood DC Ag 1; C3AR1, CC3a receptor 1; CCR7, CCR type 7; Ct, cycle threshold; Received for publication November 14, 2018. Accepted for publication June 3, 2019. DC, dendritic cell; FDR, false discovery rate; GSEA, gene set enrichment analysis; This work was supported by National Institutes of Health Grants U01AI065279 and HCV, hepatitis C virus; HIC, HIV-1 controller; IFI44L, IFN-induced protein 44 like; UM1 AI126620 (to L.J.M.). Additional support was provided by The Philadelphia IPA, Ingenuity Pathway Analysis; ISG, IFN-stimulated gene; KIR2DL1, killer cell Foundation (Robert I. Jacobs Fund), a Kean Family Professorship, Ken Nimblett and Ig-like receptor, two Ig domains and long cytoplasmic tail 1; KIR2DL2/DL3, the Summerhill Trust, AIDS funds from the Commonwealth of Pennsylvania, and KIR2DL, two domains, long cytoplasmic tail 2/3; MDC, myeloid DC; MFI, mean from the Commonwealth Universal Research Enhancement Program, Pennsylvania fluorescence intensity; miRNA, microRNA; N, primary endpoint nonresponder; NES, Department of Health, the Penn Center for AIDS Research (Grant P30 AI 045008), normalized enrichment score; NN, ISG nonresponder/primary endpoint nonre- and Wistar Cancer Center Grant P30 CA10815. The funders had no role in study sponder; PDC, plasmacytoid DC; Peg–IFN-a2a, pegylated IFN-a2a; R, primary design, data collection and analysis, decision to publish, or preparation of the endpoint responder; RN, ISG responder/primary endpoint nonresponder; RNU, nu- manuscript. cleolar RNA; RR, ISG responder/primary endpoint nonresponder; RT, room temperature. M.F., B.N.R., and A.M. performed experimental work. K.M., J.R.K., P.T., and J.M.J. selected patients. K.L. performed patient recruitment. A.V.K. and N.D. performed Ó analysis of the microarray data. K.H.M. performed the statistical analysis of immune Copyright 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 and clinical data. E.P., L.A., L.S., and L.J.M. designed the study, evaluated the results, and wrote the manuscript. All authors have read and approved the manuscript. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801511 2 INNATE CORRELATES OF IFN-a MEDIATED SUPPRESSION IN HIV as part of the anti-HIV mechanism of action (13). Short-term CD16-allophycocyanin-Cy7; 3) CD158a (killer cell Ig-like receptor, two Ig treatment with Peg–IFN-a2a added to ART in acute infection domains and long cytoplasmic tail 1 [KIR2DL1]–FITC, CD158b (KIR2DL, also led to a decrease in HIV reservoirs (24). two domains, long cytoplasmic tail 2/3 [KIR2DL2/DL3]–PE, CD3-PerCP- Cy5.5, CD94-allophycocyanin, and CD56-allophycocyanin-Cy7; 4) CD1c We and others have tested the potential for Peg–IFN-a2a im- (blood DC Ag 1 [BDCA1]–FITC, CD303 (BDCA2)–PE, CD304 (BDCA4)– munotherapy to reduce the size of the HIV reservoir (measured PE, CD11c-PerCP-Cy5.5, CD197 (CCR type 7 [CCR7])–allophycocyanin, and as the integrated HIV DNA levels) in chronic ART-suppressed CD19-allophycocyanin-Cy7; 5) CD95-FITC, CD25-PE, CD3-PerCP-Cy5.5, HIV or hepatitis C virus (HCV)/HIV–infected subjects (25–27). CD38-allophycocyanin, and CD4-allophycocyanin-Cy7; and 6) CD3- PerCP-Cy5.5, HLA-DR-allophycocyanin, and CD4-allophycocyanin-Cy7. Together, these studies suggest that IFN-a can suppress plasma Isotypes used included IgG1k-FITC, IgG1k-PE, IgG1k-PerCP-Cy5.5, + viral load and act to decrease CD4 T cell integrated HIV DNA IgG1k-allophycocyanin, and IgG1k-allophycocyanin-Cy7. All Abs were levels, as reported in our NCT00594880 clinical study (25). from Becton Dickinson (BD) Biosciences (San Diego, CA) except BDCA1- However, the mechanisms underlying the in vivo responses de- FITC and BDCA2-PE, which were from Miltenyi Biotec (San Diego, CA). scribed for our NCT00594880 clinical study remain undefined. Stainings 1–3 allowed for the assessment of markers of activation/inhibition (HLA-DR, CD94, CD25, and KIRs) on NK cell subsets (30, 31), identified as We now describe innate activity, NK cytotoxicity, and gene the following: 1) CD32CD56bright and CD32CD56dim with or without CD16, expression as correlates of retained plasma viral load suppres- and 2) CD32CD562CD16+,CD32CD56+CD16+,andCD32CD56+CD162. sion and CD4+ T cell integrated HIV DNA reduction after ART Staining 4 allowed for the assessment of maturation markers (CCR7) on DC + + interruption and Peg–IFN-a2a monotherapy. subsets (32), identified as BDCA2 BDCA4 (plasmacytoid DC [PDC]) and CD192BDCA1+CD11c+ (myeloid DC [MDC]). Finally, stainings 5 and 6 allowed for the assessment of markers of activation (i.e., CD38, CD95, CD25, Materials and Methods and HLA-DR) on T cells (CD3+CD4+ and CD3+CD42). Cells were analyzed Participants on an LSRII cytometer (BD Biosciences) by collecting .200,000 events, and data were analyzed using FlowJo software (Version 8.8.4; Tree Star, Fresh whole blood samples were obtained from 20 HIV-infected sub- Ashland, OR). Gating was originally done on singlets and then on jects on suppressive ART (with .6moat$400 CD4+ T cells/mm3 [nadir 3 “live lymphocyte” (for NK and T cells) or “all live cell” (for DC) gates $ 200 cells/mm ] and undetectable HIV viral load measurement defined by size and granularity in forward scatter and side scatter. , of 50 copies/ml at screening) participating in an open-label longitudi- Thresholds were set by isotype-matched negative controls and unstained nal study (NCT00594880) investigating the antiviral activity of 90 or cells.
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