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Cited by 165HIV Research and TreatmentHIV/AIDS drug development and treatmentVirus-based gene therapy research

HIV rebound is predominantly fueled by genetically identical viral expansions from diverse reservoirs

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De Scheerder, Marie-Angélique, Vrancken, Bram, Dellicour, Simon, Schlub, Timothy, Lee, Eunok, Shao, Wei, Rutsaert, Sofie, Verhofstede, Chris +10 more·2019·Cell Host & Microbe
DOI 10.1016/j.chom.2019.08.003PMC PMC11021134
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Abstract

Viral rebound upon stopping combined antiretroviral therapy poses a major barrier toward an HIV cure. Cellular and anatomical sources responsible for reinitiating viral replication remain a subject of ardent debate, despite extensive research efforts. To unravel the source of rebounding viruses, we conducted a large-scale HIV-STAR (HIV-1 sequencing before analytical treatment interruption to identify the anatomically relevant HIV reservoir) clinical trial. We collected samples from 11 participants and compared the genetic composition of (pro)viruses collected under treatment from different cellular and anatomical compartments with that of plasma viruses sampled during analytical treatment interruption. We found a remarkably heterogeneous source of viral rebound. In addition, irrespective of the compartment or cell subset, genetically identical viral expansions played a significant role in viral rebound. Our study suggests that although there does not seem to be a primary source for rebound HIV, cellular proliferation is an important driver of HIV persistence and should therefore be considered in future curative strategies.

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Research works printed but not linked: 66

  1. Abascal F, Zardoya R, and Telford MJ (2010). TranslatorX: multiple alignment of nucleotide sequences guided by amino acid translations. Nucleic Acids Res. 38, W7– w13. PMC2896173 20435676
  2. Banga R, Procopio FA, Noto A, Pollakis G, Cavassini M, Ohmiti K, Corpataux JM, de Leval L, Pantaleo G, and Perreau M (2016). PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. 22, 754– 761. 27239760
  3. Banga R, Procopio FA, Ruggiero A, Noto A, Ohmiti K, Cavassini M, Corpataux JM, Paxton WA, Pollakis G, and Perreau M (2018). Blood CXCR3(+) CD4 T cells are enriched in inducible replication competent HIV in aviremic antiretroviral therapy-treated individuals. Front. Immunol. 9, 144. PMC5807378 29459864
  4. Barton K, Hiener B, Winckelmann A, Rasmussen TA, Shao W, Byth K, Lanfear R, Solomon A, McMahon J, Harrington S, (2016). Broad activation of latent HIV-1 in vivo. Nat. Commun. 7, 12731. PMC5025526 27605062
  5. Bielejec F, Baele G, Rodrigo AG, Suchard MA, and Lemey P (2016). Identifying predictors of time-inhomogeneous viral evolutionary processes. Virus Evol. 2, vew023. PMC5072463 27774306
  6. Bloomquist EW, Lemey P, and Suchard MA (2010). Three roads diverged? Routes to phylogeographic inference. Trends Ecol. Evol. 25, 626– 632. PMC2956787 20863591
  7. Bui JK, Halvas EK, Fyne E, Sobolewski MD, Koontz D, Shao W, Luke B, Hong FF, Kearney MF, and Mellors JW (2017). Ex vivo activation of CD4+ T-cells from donors on suppressive ART can lead to sustained production of infectious HIV-1 from a subset of infected cells. PLoS Pathog. 13, e1006230. PMC5338860 28225830
  8. Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, Martin-Gayo E, Leng J, Henrich TJ, Li JZ, (2014). HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat. Med. 20, 139– 142. PMC3959167 24412925
  9. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, (2009). HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med. 15, 893– 900. PMC2859814 19543283
  10. Chun TW, Justement JS, Murray D, Hallahan CW, Maenza J, Collier AC, Sheth PM, Kaul R, Ostrowski M, Moir S, (2010). Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 24, 2803– 2808. PMC3154092 20962613
  11. Clarridge KE, Blazkova J, Einkauf K, Petrone M, Refsland EW, Justement JS, Shi V, Huiting ED, Seamon CA, Lee GQ, (2018). Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals. PLoS Pathog. 14, e1006792. PMC5764487 29324842
  12. Cock PJA, Antao T, Chang JT, Chapman BA, Cox CJ, Dalke A, Friedberg I, Hamelryck T, Kauff F, Wilczynski B, (2009). Biopython: freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics 25, 1422– 1423. PMC2682512 19304878
  13. Cohen YZ, Lorenzi JCC, Krassnig L, Barton JP, Burke L, Pai J, Lu CL, Mendoza P, Oliveira TY, Sleckman C, (2018). Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. J. Exp. Med. 215, 2311– 2324. PMC6122972 30072495
  14. Cohn LB, Silva IT, Oliveira TY, Rosales RA, Parrish EH, Learn GH, Hahn BH, Czartoski JL, McElrath MJ, Lehmann C, (2015). HIV-1 integration landscape during latent and active infection. Cell 160, 420– 432. PMC4371550 25635456
  15. Dahl V, Peterson J, Fuchs D, Gisslen M, Palmer S, and Price RW (2014). Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 28, 2251– 2258. PMC4492794 25022595
  16. Dellicour S, and Mardulyn P (2014). Spads 1.0: a toolbox to perform spatial analyses on DNA sequence data sets. Mol. Ecol. Resour. 14, 647– 651. 24215429
  17. Descours B, Petitjean G, López-Zaragoza JL, Bruel T, Raffel R, Psomas C, Reynes J, Lacabaratz C, Levy Y, Schwartz O, (2017). CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature 543, 564– 567. 28297712
  18. Edgar RC (2004). MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792– 1797. PMC390337 15034147
  19. Eisele E, and Siliciano RF (2012). Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 37, 377– 388. PMC3963158 22999944
  20. Faria NR, Suchard MA, Rambaut A, and Lemey P (2011). Toward a quantitative understanding of viral phylogeography. Curr. Opin. Virol. 1, 423– 429. PMC3312803 22440846
  21. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, (1997). Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295– 1300. 9360927
  22. Garner SA, Rennie S, Ananworanich J, Dube K, Margolis DM, Sugarman J, Tressler R, Gilbertson A, and Dawson L (2017). Interrupting antiretroviral treatment in HIV cure research: scientific and ethical considerations. J. Virus Erad. 3, 82– 84. PMC5384270 28435691
  23. Guindon S, and Gascuel O (2003). A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst. Biol. 52, 696– 704. 14530136
  24. Henrich TJ, Hatano H, Bacon O, Hogan LE, Rutishauser R, Hill A, Kearney MF, Anderson EM, Buchbinder SP, Cohen SE, (2017). HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study. PLoS Med. 14, e1002417. PMC5675377 29112956
  25. Hiener B, Horsburgh BA, Eden JS, Barton K, Schlub TE, Lee E, von Stockenstrom S, Odevall L, Milush JM, Liegler T, (2017). Identification of genetically intact HIV-1 proviruses in specific CD4(+) T cells from effectively treated participants. Cell Rep. 21, 813– 822. PMC5960642 29045846
  26. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, and Siliciano RF (2013). Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540– 551. PMC3896327 24243014
  27. Hosmane NN, Kwon KJ, Bruner KM, Capoferri AA, Beg S, Rosenbloom DI, Keele BF, Ho YC, Siliciano JD, and Siliciano RF (2017). Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J. Exp. Med. 214, 959– 972. PMC5379987 28341641
  28. Hothorn Torsten BF, and Peter W (2008). Simultaneous inference in general parametric models. Biometrical J. 50, 346– 363. 18481363
  29. Jensen MA, Li FS, van ‘t Wout AB, Nickle DC, Shriner D, He HX, McLaughlin S, Shankarappa R, Margolick JB, and Mullins JI (2003). Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J. Virol. 77, 13376– 13388. PMC296044 14645592
  30. Josefsson L, Eriksson S, Sinclair E, Ho T, Killian M, Epling L, Shao W, Lewis B, Bacchetti P, Loeb L, (2012). Hematopoietic precursor cells isolated from patients on long-term suppressive HIV therapy did not contain HIV-1 DNA. J. Infect. Dis. 206, 28– 34. PMC3415927 22536001
  31. Josefsson L, von Stockenstrom S, Faria NR, Sinclair E, Bacchetti P, Killian M, Epling L, Tan A, Ho T, Lemey P, (2013). The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc. Natl. Acad. Sci. USA 110, E4987– E4996. PMC3870728 24277811
  32. Kandathil AJ, Sugawara S, and Balagopal A (2016). Are T cells the only HIV-1 reservoir? Retrovirology 13. PMC5175311 27998285
  33. Kearney M, Maldarelli F, Shao W, Margolick JB, Daar ES, Mellors JW, Rao V, Coffin JM, and Palmer S (2009). Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals. J. Virol. 83, 2715– 2727. PMC2648286 19116249
  34. Kearney MF, Wiegand A, Shao W, Coffin JM, Mellors JW, Lederman M, Gandhi RT, Keele BF, and Li JZ (2016). Origin of rebound plasma HIV includes cells with identical proviruses that are transcriptionally active before stopping of antiretroviral therapy. J. Virol. 90, 1369– 1376. PMC4719635 26581989
  35. Kearney MF, Wiegand A, Shao W, McManus WR, Bale MJ, Luke B, Maldarelli F, Mellors JW, and Coffin JM (2017). Ongoing HIV replication During ART reconsidered. Open Forum Infect. Dis. 4, ofx173. PMC6172598 30310821
  36. Khoury G, Fromentin R, Solomon A, Hartogensis W, Killian M, Hoh R, Somsouk M, Hunt PW, Girling V, Sinclair E, (2017). Human immunodeficiency virus persistence and T-cell activation in blood, rectal, and lymph node tissue in human immunodeficiency virus-infected individuals receiving suppressive antiretroviral therapy. J. Infect. Dis. 215, 911– 919. PMC5407052 28453847
  37. Kiselinova M, De Spiegelaere W, Buzon MJ, Malatinkova E, Lichterfeld M, and Vandekerckhove L (2016). Integrated and total HIV-1 DNA predict ex vivo viral outgrowth. PLoS Pathog. 12, e1005472. PMC4777389 26938995
  38. Larsson A (2014). AliView: a fast and lightweight alignment viewer and editor for large datasets. Bioinformatics 30, 3276– 3278. PMC4221126 25095880
  39. Laskey SB, Pohlmeyer CW, Bruner KM, and Siliciano RF (2016). Evaluating clonal expansion of HIV-infected cells: optimization of PCR strategies to predict clonality. PLoS Pathog. 12, e1005689. PMC4975415 27494508
  40. Lederman MM, Cannon PM, Currier JS, June CH, Kiem HP, Kuritzkes DR, Lewin SR, Margolis DM, McCune JM, Mellors JW, (2016). A cure for HIV infection: “not in my lifetime” or “just around the corner”? Pathog. Immun. 1, 154– 164. PMC5033048 27668293
  41. Lee GQ, Orlova-Fink N, Einkauf K, Chowdhury FZ, Sun X, Harrington S, Kuo HH, Hua S, Chen HR, Ouyang Z, (2017a). Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. J. Clin. Invest. 127, 2689– 2696. PMC5490740 28628034
  42. Lee SK, Zhou S, Baldoni PL, Spielvogel E, Archin NM, Hudgens MG, Margolis DM, and Swanstrom R (2017b). Quantification of the latent HIV-1 reservoir using ultra deep sequencing and primer ID in a viral outgrowth assay. J. Acquir. Immune Defic. Syndr. 74, 221– 228. PMC5233602 27683060
  43. Letunic I, and Bork P (2016). Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res. 44, W242– W245. PMC4987883 27095192
  44. Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J, Pond SLK, Chung YS, Penugonda S, Chipman JG, Fletcher CV, (2016). Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530, 51– 56. PMC4865637 26814962
  45. Lu CL, Pai JA, Nogueira L, Mendoza P, Gruell H, Oliveira TY, Barton J, Lorenzi JCC, Cohen YZ, Cohn LB, (2018). Relationship between intact HIV-1 proviruses in circulating CD4(+) T cells and rebound viruses emerging during treatment interruption. Proc. Natl. Acad. Sci. USA 115, E11341– E11348. PMC6275529 30420517
  46. Margolis DM, Garcia JV, Hazuda DJ, and Haynes BF (2016). Latency reversal and viral clearance to cure HIV-1. Science 353, aaf6517. PMC5021637 27463679
  47. Martin DP, Murrell B, Golden M, Khoosal A, and Muhire B (2015). RDP4: detection and analysis of recombination patterns in virus genomes. Virus Evol. 1, vev003. PMC5014473 27774277
  48. McGary CS, Deleage C, Harper J, Micci L, Ribeiro SP, Paganini S, Kuri-Cervantes L, Benne C, Ryan ES, Balderas R, (2017). CTLA-4(+)PD-1(−) memory CD4(+) T cells critically contribute to viral persistence in antiretroviral therapy-suppressed, SIV-infected rhesus macaques. Immunity 47, 776– 788.e5. PMC5679306 29045906
  49. Mendoza P, Gruell H, Nogueira L, Pai JA, Butler AL, Millard K, Lehmann C, Suárez I, Oliveira TY, Lorenzi JCC, (2018). Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479– 484. PMC6166473 30258136
  50. Minin VN, and Suchard MA (2008a). Counting labeled transitions in continuous-time Markov models of evolution. J. Math. Biol. 56, 391– 412. 17874105
  51. Minin VN, and Suchard MA (2008b). Fast, accurate and simulation-free stochastic mapping. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3985– 3995. PMC2607419 18852111
  52. Morón-López S, Puertas MC, Gálvez C, Navarro J, Carrasco A, Esteve M, Manyé J, Crespo M, Salgado M, and Martinez-Picado J (2017). Sensitive quantification of the HIV-1 reservoir in gut-associated lymphoid tissue. PloS One 12, e0175899. PMC5393620 28414780
  53. Nei M, and Li WH (1979). Mathematical model for studying genetic variation in terms of restriction endonucleases. Proc. Natl. Acad. Sci. USA 76, 5269– 5273. PMC413122 291943
  54. Palmer S, Kearney M, Maldarelli F, Halvas EK, Bixby CJ, Bazmi H, Rock D, Falloon J, Davey RT Jr., Dewar RL, (2005). Multiple, linked human immunodeficiency virus type 1 drug resistance mutations in treatment-experienced patients are missed by standard genotype analysis. J. Clin. Microbiol. 43, 406– 413. PMC540111 15635002
  55. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, Dewar RL, Planta A, Liu S, Metcalf JA, (2003). New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J. Clin. Microbiol. 41, 4531– 4536. PMC254331 14532178
  56. Parker J, Rambaut A, and Pybus OG (2008). Correlating viral phenotypes with phylogeny: accounting for phylogenetic uncertainty. Infect. Genet. Evol. 8, 239– 246. 17921073
  57. Ronquist F, Teslenko M, van der Mark P, Ayres DL, Darling A, Höhna S, Larget B, Liu L, Suchard MA, and Huelsenbeck JP (2012). MrBayes 3.2: efficient Bayesian phylogenetic inference and model choice across a large model space. Syst. Biol. 61, 539– 542. PMC3329765 22357727
  58. Rosenbloom DIS, Hill AL, Laskey SB, and Siliciano RF (2017). Re-evaluating evolution in the HIV reservoir. Nature 551, E6– E9. PMC6103791 29168805
  59. Rothenberger MK, Keele BF, Wietgrefe SW, Fletcher CV, Beilman GJ, Chipman JG, Khoruts A, Estes JD, Anderson J, Callisto SP, (2015). Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc. Natl. Acad. Sci. USA 112, E1126– E1134. PMC4364237 25713386
  60. Salantes DB, Zheng Y, Mampe F, Srivastava T, Beg S, Lai J, Li JZ, Tressler RL, Koup RA, Hoxie J, (2018). HIV-1 latent reservoir size and diversity are stable following brief treatment interruption. J. Clin. Invest. 128, 3102– 3115. PMC6026010 29911997
  61. von Stockenstrom S, Odevall L, Lee E, Sinclair E, Bacchetti P, Killian M, Epling L, Shao W, Hoh R, Ho T, (2015). Longitudinal genetic characterization reveals that cell proliferation maintains a persistent HIV Type 1 DNA pool During effective HIV therapy. J. Infect. Dis. 212, 596– 607. PMC4539896 25712966
  62. Wang TH, Donaldson YK, Brettle RP, Bell JE, and Simmonds P (2001). Identification of shared populations of human immunodeficiency virus type 1 infecting microglia and tissue macrophages outside the central nervous system. J. Virol. 75, 11686– 11699. PMC114755 11689650
  63. Wang XQ, and Palmer S (2018). Single-molecule techniques to quantify and genetically characterise persistent HIV. Retrovirology 15, 3. PMC5761141 29316955
  64. Wang Z, Gurule EE, Brennan TP, Gerold JM, Kwon KJ, Hosmane NN, Kumar MR, Beg SA, Capoferri AA, Ray SC, (2018). Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc. Natl. Acad. Sci. USA 115, E2575– E2584. PMC5856552 29483265
  65. Winckelmann A, Barton K, Hiener B, Schlub TE, Shao W, Rasmussen TA, Østergaard L, Søgaard OS, Tolstrup M, and Palmer S (2017). Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations. AIDS Lond. Engl. 31, 771– 779. PMC5345886 28272134
  66. Yang Z (1994). Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods. J. Mol. Evol. 39, 306– 314. 7932792

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Authors
De Scheerder, M.-A., Vrancken, B., Dellicour, S., Schlub, T., Lee, E., Shao, W., Rutsaert, S., Verhofstede, C., Kerre, T., Malfait, T., Hemelsoet, D., Coppens, M., Dhondt, A., De Looze, D., Vermassen, F., Lemey, P., Palmer, S., & Vandekerckhove, L.
Affiliations
  • KU Leuven (BE)
  • Université Libre de Bruxelles (BE)
  • The University of Sydney (AU)
  • Frederick National Laboratory for Cancer Research (US)
  • Ghent University Hospital (BE)
Corresponding author
Vandekerckhove, Linos
ORCID
Venue
Cell Host & Microbe
Publisher
Elsevier BV
Published
2019-09
Volume
26
Issue
3
Pages
347-358.e7
ISSN
1931-3128 (ISSN-L)
DOI
10.1016/j.chom.2019.08.003
PMC
PMC11021134
OpenAlex
W2970368853
Cited by
165
References
5
Citations by year
2026: 16 · 2025: 28 · 2024: 16 · 2023: 21 · 2022: 24 · 2021: 24 · 2020: 32 · 2019: 4
FWCI
11.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Host & Microbe (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (publishedVersion, other-oa)
  • Ghent University Academic Bibliography (Ghent University) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion)
Funders
Merck Sharp and Dohme
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
HIV rebound, HIV reservoir, treatment interruption, HIV cure, HIV-1 provirus, viral quasispecies, cell proliferation, HIV persistence, viral reactivation, anatomical compartments
MeSH terms
Bone Marrow, Cerebrospinal Fluid, Female, Genes, Viral, Humans, Kinetics, Lymph Nodes, Lymphoid Tissue, Male, Plasma, Virus Replication, HIV-1, HIV Infections, Viral Load, Anti-Retroviral Agents, Cell Proliferation, Vascular Access Devices

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