Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice

English version

Autoři: John D. Ventura ^aff001; Jagadish Beloor ^aff002; Edward Allen ^aff003; Tongyu Zhang ^aff004; Kelsey A. Haugh ^aff001; Pradeep D. Uchil ^aff001; Christina Ochsenbauer ^aff005; Collin Kieffer ^aff004; Priti Kumar ^aff002; Thomas J. Hope ^aff003; Walther Mothes ^aff001
Působiště autorů: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, United States of America ^aff001; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States of America ^aff002; Department of Cellular and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America ^aff003; School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois at Urbana-Campaign, Urbana, IL, United States of America ^aff004; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America ^aff005
Vyšlo v časopise: Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008161
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008161

Souhrn

Non-invasive bioluminescent imaging (NIBLI) of HIV-1 infection dynamics allows for real-time monitoring of viral spread and the localization of infected cell populations in living animals. In this report, we describe full-length replication-competent GFP and Nanoluciferase (Nluc) expressing HIV-1 reporter viruses from two clinical transmitted / founder (T/F) stains: TRJO.c and Q23.BG505. By infecting humanized mice with these HIV-1 T/F reporter viruses, we were able to directly monitor longitudinal viral spread at whole-animal resolution via NIBLI at a sensitivity of as few as 30–50 infected cells. Bioluminescent signal strongly correlated with HIV-1 infection and responded proportionally to virus suppression in vivo in animals treated daily with a combination antiretroviral therapy (cART) regimen. Longitudinal NIBLI following cART withdrawal visualized tissue-sites that harbored virus during infection recrudescence. Notably, we observed rebounding infection in the same lymphoid tissues where infection was first observed prior to ART treatment. Our work demonstrates the utility of our system for studying in vivo viral infection dynamics and identifying infected tissue regions for subsequent analyses.

Klíčová slova:

Blood plasma – Flow cytometry – HIV-1 – Infection imaging – Internal ribosome entry site – Reporter genes – Spleen – T cells

Zdroje

1. Stacer AC, Nyati S, Moudgil P, Iyengar R, Luker KE, Rehemtulla A, et al. NanoLuc reporter for dual luciferase imaging in living animals. Mol Imaging. 2013;12: 1–13. doi: 10.2310/7290.2013.00062

2. Avci P, Karimi M, Sadasivam M, Antunes-Melo WC, Carrasco E, Hamblin MR. In-vivo monitoring of infectious diseases in living animals using bioluminescence imaging. Virulence. 2018;9: 28–63. doi: 10.1080/21505594.2017.1371897 28960132

3. Demidova TN, Gad F, Zahra T, Francis KP, Hamblin MR. Monitoring photodynamic therapy of localized infections by bioluminescence imaging of genetically engineered bacteria. J Photochem Photobiol B Biol. 2005;81: 15–25. doi: 10.1016/j.jphotobiol.2005.05.007 16040251

4. Nham T, Filali S, Danne C, Derbise A, Carniel E. Imaging of bubonic plague dynamics by in vivo tracking of bioluminescent yersinia pestis. PLoS One. 2012;7. doi: 10.1371/journal.pone.0034714 22496846

5. Vecchio D, Dai T, Huang L, Fantetti L, Roncucci G, Hamblin MR. Antimicrobial photodynamic therapy with RLP068 kills methicillin-resistant Staphylococcus aureus and improves wound healing in a mouse model of infected skin abrasion PDT with RLP068/Cl in infected mouse skin abrasion. J Biophotonics. 2013;6: 733–742. doi: 10.1002/jbio.201200121 22987338

6. Zaitseva M, Kapnick S, Golding H. Measurements of vaccinia virus dissemination using whole body imaging: Approaches for predicting of lethality in challenge models and testing of vaccines and antiviral treatments. Methods Mol Biol. 2012;890: 161–176. doi: 10.1007/978-1-61779-876-4_10 22688767

7. Luker GD, Prior JL, Song J, Pica CM, Leib DA. Bioluminescence imaging reveals systemic dissemination of herpes simplex virus type 1 in the absence of interferon receptors. J Virol. 2003;77: 11082–11093. doi: 10.1128/JVI.77.20.11082-11093.2003 14512556

8. Henriques C, Castro DP, Gomes LHF, Garcia ES, De Souza W. Bioluminescent imaging of Trypanosoma cruzi infection in Rhodnius prolixus. Parasites and Vectors. 2012;5. doi: 10.1186/1756-3305-5-214 23013827

9. Americo JL, Sood CL, Cotter CA, Vogel JL, Kristie TM, Moss B, et al. Susceptibility of the wild-derived inbred CAST/Ei mouse to infection by orthopoxviruses analyzed by live bioluminescence imaging. Virology. 2014;449: 120–132. doi: 10.1016/j.virol.2013.11.017 24418545

10. Sun C, Gardner CL, Watson AM, Ryman KD, Klimstra WB. Stable, High-Level Expression of Reporter Proteins from Improved Alphavirus Expression Vectors To Track Replication and Dissemination during Encephalitic and Arthritogenic Disease. J Virol. 2014;88: 2035–2046. doi: 10.1128/JVI.02990-13 24307590

11. Karlsson EA, Meliopoulos VA, Savage C, Livingston B, Mehle A, Schultz-Cherry S. Visualizing real-time influenza virus infection, transmission and protection in ferrets. Nat Commun. 2015;6: 1–10. doi: 10.1038/ncomms7378 25744559

12. Tran V, Moser LA, Poole DS, Mehle A. Highly Sensitive Real-Time In Vivo Imaging of an Influenza Reporter Virus Reveals Dynamics of Replication and Spread. J Virol. 2013;87: 13321–13329. doi: 10.1128/JVI.02381-13 24089552

13. Santangelo PJ, Rogers KA, Zurla C, Blanchard EL, Gumber S, Strait K, et al. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat Methods. 2015;12: 427–432. doi: 10.1038/nmeth.3320 25751144

14. Hall MP, Unch J, Binkowski BF, Valley MP, Butler BL, Wood MG, et al. Engineered luciferase reporter from a deep sea shrimp utilizing a novel imidazopyrazinone substrate. ACS Chem Biol. 2012;7: 1848–1857. doi: 10.1021/cb3002478 22894855

15. Ochsenbauer C, Edmonds TG, Ding H, Keele BF, Decker J, Salazar MG, et al. 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. 2012;86: 2715–2728. doi: 10.1128/JVI.06157-11 22190722

16. Wu X, Parast AB, Richardson B a, Nduati R, John-stewart G, Mbori-ngacha D, et al. Neutralization escape variants of human immunodeficiency virus type 1 are transmitted frommother to infant. J Virol. 2006;80: 835–844. doi: 10.1128/JVI.80.2.835-844.2006 16378985

17. Alberti MO, Jones JJ, Miglietta R, Ding H, Bakshi RK, Edmonds TG, et al. Optimized Replicating Renilla Luciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function. AIDS Res Hum Retroviruses. 2015;31: 1278–1296. doi: 10.1089/aid.2015.0074 26101895

18. Le Gall S, Prevost MC, Heard JM, Schwartz O. Human immunodeficiency virus type I Nef independently affects virion incorporation of major histocompatibility complex class I molecules and virus infectivity. Virology. 1997;229: 295–301. S0042682296984172 [pii] doi: 10.1006/viro.1996.8417 9123874

19. Greenberg ME, Lafrate AJ, Skowronski J. The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes. EMBO J. 1998;17: 2777–2789. doi: 10.1093/emboj/17.10.2777 9582271

20. Mariani R, Skowronski J, Singer MF. CD4 down-regulation by nef alleles isolated from human immunodeficiency virus type 1-infected individuals. Proc Natl Acad Sci USA. 1993;90: 5549–5553. doi: 10.1073/pnas.90.12.5549 8516299

21. Garcia JV, Miller AD. Serine phosphorylation-independent downregulation of cell-surface CD4 by nef. Nature. 1991;350: 508–511. doi: 10.1038/350508a0 2014052

22. Schwartz O, Maréchal V, Le Gall S, Lemonnier F, Heard JM. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med. 1996;2: 338–342. doi: 10.1038/nm0396-338 8612235

23. Ochsenbauer-Jambor C, Jones J, Heil M, Zammit KP, Kutsch O. T-cell line for HIV drug screening using EGFP as a quantitative marker of HIV-1 replication. Biotechniques. 2006;40: 91–100. doi: 10.2144/000112072 16454046

24. Lenassi M, Cagney G, Liao M, Vaupotič T, Bartholomeeusen K, Cheng Y, et al. HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells. Traffic. 2010;11: 110–122. doi: 10.1111/j.1600-0854.2009.01006.x 19912576

25. Acheampong EA, Parveen Z, Muthoga LW, Kalayeh M, Mukhtar M, Pomerantz RJ. Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases. J Virol. 2005;79: 4257–4269. doi: 10.1128/JVI.79.7.4257-4269.2005 15767427

26. Fujii Y, Otake K, Tashiro M, Adachi A. In vitro cytocidal effects of human immunodeficiency virus type 1 Nef on unprimed human CD4+ T cells without MHC restriction. J Gen Virol. 1996;77: 2943–2951. doi: 10.1099/0022-1317-77-12-2943 9000084

27. Fujii Y, Otake K, Tashiro M, Adachi A. Soluble Nef antigen of HIV-1 is cytotoxic for human CD4+ T cells. FEBS Lett. 1996;393: 93–96. doi: 10.1016/0014-5793(96)00859-9 8804432

28. Murooka TT, Deruaz M, Marangoni F, Vrbanac VD, Seung E, Von Andrian UH, et al. HIV-infected T cells are migratory vehicles for viral dissemination. Nature. 2012;490: 283–289. doi: 10.1038/nature11398 22854780

29. Schindler M, Mu J, Kirchhoff F. Human Immunodeficiency Virus Type 1 Inhibits DNA Damage-Triggered Apoptosis by a Nef-Independent Mechanism. J Virol. 2005;79: 5489–5498. doi: 10.1128/JVI.79.9.5489-5498.2005 15827163

30. Law KM, Komarova NL, Yewdall AW, Lee RK, Herrera OL, Wodarz D, et al. In Vivo HIV-1 Cell-to-Cell Transmission Promotes Multicopy Micro-compartmentalized Infection. Cell Rep. 2016;15: 2771–2783. doi: 10.1016/j.celrep.2016.05.059 27292632

31. Symeonides M, Murooka TT, Bellfy LN, Roy NH, Mempel TR, Thali M. HIV-1-induced small T cell syncytia can transfer virus particles to target cells through transient contacts. Viruses. 2015;7: 6590–6603. doi: 10.3390/v7122959 26703714

32. Vermeire J, Naessens E, Vanderstraeten H, Landi A, Iannucci V, van Nuffel A, et al. Quantification of Reverse Transcriptase Activity by Real-Time PCR as a Fast and Accurate Method for Titration of HIV, Lenti- and Retroviral Vectors. PLoS One. 2012;7. doi: 10.1371/journal.pone.0050859 23227216

33. Pizzato M, Erlwein O, Bonsall D, Kaye S, Muir D, McClure MO. A one-step SYBR Green I-based product-enhanced reverse transcriptase assay for the quantitation of retroviruses in cell culture supernatants. J Virol Methods. 2009;156: 1–7. doi: 10.1016/j.jviromet.2008.10.012 19022294

34. Whitney JB, Hill AL, Sanisetty S, Penaloza-Macmaster P, Liu J, Shetty M, et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014;512: 74–77. doi: 10.1038/nature13594 25042999

35. Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC, Casares S, et al. Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary. AIDS Res Hum Retroviruses. 2016;32: 109–119. doi: 10.1089/AID.2015.0258 26670361

36. Whitney JB, Lim SY, Osuna CE, Kublin JL, Chen E, Yoon G, et al. Prevention of SIVmac251 reservoir seeding in rhesus monkeys by early antiretroviral therapy. Nat Commun. 2018;9. doi: 10.1038/s41467-018-07881-9 30575753

37. Baxter AE, Russell RA, Duncan CJA, Moore MD, Willberg CB, Pablos JL, et al. Macrophage infection via selective capture of HIV-1-infected CD4+ T cells. Cell Host Microbe. 2014;16: 711–721. doi: 10.1016/j.chom.2014.10.010 25467409

38. Bracq L, Xie M, Lambelé M, Vu L-T, Matz J, Schmitt A, et al. T Cell-Macrophage Fusion Triggers Multinucleated Giant Cell Formation for HIV-1 Spreading. J Virol. 2017;91. doi: 10.1128/jvi.01237-17 28978713

39. Carter CA, Ehrlich LS. Cell Biology of HIV-1 Infection of Macrophages. Annu Rev Microbiol. 2008;62: 425–443. doi: 10.1146/annurev.micro.62.081307.162758 18785842

40. Arrildt KT, LaBranche CC, Joseph SB, Dukhovlinova EN, Graham WD, Ping L-H, et al. Phenotypic Correlates of HIV-1 Macrophage Tropism. J Virol. 2015;89: 11294–11311. doi: 10.1128/JVI.00946-15 26339058

41. Gibson DG, Young L, Chuang RY, Venter JC, Hutchison CA, Smith HO. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods. 2009;6: 343–345. doi: 10.1038/nmeth.1318 19363495

42. Herschhorn A, Ma X, Gu C, Ventura JD, Castillo-Menendez L, Melillo B, et al. Release of GP120 restraints leads to an entry-competent intermediate state of the HIV-1 envelope glycoproteins. MBio. 2016;7: 1–12. doi: 10.1128/mBio.01598-16 27795397

43. Kieffer C, Ladinsky MS, Ninh A, Galimidi RP, Bjorkman PJ. Longitudinal imaging of hiv-1 spread in humanized mice with parallel 3D immunofluorescence and electron tomography. Elife. 2017;6: 1–24. doi: 10.7554/eLife.23282.001

44. Susaki EA, Tainaka K, Perrin D, Kishino F, Tawara T, Watanabe TM, et al. Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis. Cell. 2014;157: 726–39. doi: 10.1016/j.cell.2014.03.042 24746791