Antiretroviral Treatment for HIV Elite Controllers?
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Abstract
In most HIV-infected persons, the natural history of untreated infection is one of sustained viremia, progressive CD4 T cell depletion with resultant morbidity and mortality. The advent of effective combination antiretroviral therapy (ART) that controls HIV replication has altered this landscape dramatically. Yet a rare population of HIV-infected persons—elite controllers (EC)—can control HIV replication such that plasma levels of virus are “undetectable” without ART. The EC phenotype is heterogeneous, with some subjects durably controlling the virus—persistent elite controllers—and some eventually losing viral control—transient elite controllers. Overall, EC tend to have robust HIV-specific T cell responses and in some cases, mainly in transient elite controllers, elevated activation and inflammation indices that diminish with ART suggesting that endogenous defenses against this persistent pathogen come at the cost of heightened activation/inflammation. A limited data set suggests that cardiovascular disease risk as well as the occurrence of other morbid events may be greater in the overall EC population than in treated HIV infection. ART in EC decreases activation indices but does not appear to increase circulating CD4 T cell numbers nor do we know if it alters clinical outcomes. Thus, it is difficult to recommend or discourage a decision to start ART in the EC population but the authors lean toward treatment particularly in those EC whose activation indices are high and those who are progressively losing circulating CD4 T cell numbers. Biomarkers that can reliably predict loss of virologic control and immune failure are needed.
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References
1. Blankson JN. Effector mechanisms in HIV-1 infected elite controllers: highly active immune responses? Antiviral research. 2010;85(1):295-302. PubMed PMID: PMC2814919. doi: 10.1016/j.antiviral.2009.08.007
2. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity. 2007;27(3):406-16. PubMed PMID. doi: 10.1016/j.immuni.2007.08.010
3. Gonzalo-Gil E, Ikediobi U, Sutton RE. Mechanisms of Virologic Control and Clinical Characteristics of HIV+ Elite/Viremic Controllers. The Yale journal of biology and medicine. 2017;90(2):245-59. PubMed PMID: PMC5482301.
4. Lambotte O, Boufassa F, Madec Y, Nguyen A, Goujard C, Meyer L, Rouzioux C, Venet A, Delfraissy JF. HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2005;41(7):1053-6. PubMed PMID. doi: 10.1086/433188
5. Okulicz JF, Lambotte O. Epidemiology and clinical characteristics of elite controllers. Current opinion in HIV and AIDS. 2011;6(3):163-8. PubMed PMID. doi: 10.1097/COH.0b013e328344f35e
6. Olson Ashley D. Olson ,Laurence Meyer, Maria Prins, Rodolphe Thiebaut, Deepti Gurdasani, Marguerite Guiguet, Marie-Laure Chaix, Pauli Amornkul, Abdel Babiker, Manjinder S. Sandhu, Kholoud Porter, for C. A. S. C. A. D. E. Collaboration in EuroCoord. An evaluation of HIV elite controller definitions within a large seroconverter cohort collaboration. Plos One. 2014;9(1):e86719.
7. Gurdasani D(1), Iles L, Dillon DG, Young EH, Olson AD, Naranbhai V, Fidler S, Gkrania-Klotsas E, Post FA, Kellam P, Porter K, Sandhu MS. A systematic review of definitions of extreme phenotypes of HIV control andprogression. AIDS. 2014 Jan 14;28(2):149-62.
8. Chereau F, Madec Y, Sabin C, Obel N, Ruiz-Mateos E, Chrysos G, Fidler S, Lehmann C, Zangerle R, Wittkop L, Reiss P, Hamouda O, Estrada Perez V, Leal M, Mocroft A, Garcia De Olalla P, Ammassari A, D'Arminio Monforte A, Mussini C, Segura F, Castagna A, Cavassini M, Grabar S, Morlat P, De Wit S, Lambotte O, Meyer L; HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD. Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers. PLoS One. 2017;12(4):e0173893.
9. Canoui E, Lecuroux C, Avettand-Fenoel V, Gousset M, Rouzioux C, Saez-Cirion A, Meyer L, Boufassa F, Lambotte O, Noel N. A Subset of Extreme Human Immunodeficiency Virus (HIV) Controllers Is Characterized by a Small HIV Blood Reservoir and a Weak T-Cell Activation Level. Open forum infectious diseases. 2017;4(2):ofx064. PubMed PMID: PMC5450900. doi: 10.1093/ofid/ofx064
10. Pernas M, Tarancon-Diez L, Rodriguez-Gallego E, Gomez J, Prado JG, Casado C, Dominguez-Molina B, Olivares I, Coiras M, Leon A, Rodriguez C, Benito JM, Rallon N, Plana M, Martinez-Madrid O, Dapena M, Iribarren JA, Del Romero J, Garcia F, Alcami J, Munoz-Fernandez MA, Vidal F, Leal M, Lopez-Galindez C, Ruiz-Mateos E. Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection. Journal of virology. 2017. PubMed PMID: PMC5809746. doi: 10.1128/jvi.01805-17
11 Rodriguez-Gallego E, Tarancon-Diez L, Garcia F, Del Romero J, Benito JM, Alba V, Herrero P, Rull A, Dominguez-Molina B, Martinez-Madrid O, Martin-Pena L, Pulido F, Leon A, Rodriguez C, Rallon N, Peraire J, Vilades C, Leal M, Vidal F, Ruiz-Mateos E. Proteomic Profile Associated With Loss of Spontaneous Human Immunodeficiency Virus Type 1 Elite Control. The Journal of infectious diseases. 2019;219(6):867-76. PubMed PMID. doi: 10.1093/infdis/jiy599
12. Mendoza D, Johnson SA, Peterson BA, Natarajan V, Salgado M, Dewar RL, Burbelo PD, Doria-Rose NA, Graf EH, Greenwald JH, Hodge JN, Thompson WL, Cogliano NA, Chairez CL, Rehm CA, Jones S, Hallahan CW, Kovacs JA, Sereti I, Sued O, Peel SA, O'Connell RJ, O'Doherty U, Chun TW, Connors M, Migueles SA. Comprehensive analysis of unique cases with extraordinary control over HIV replication. Blood. 2012;119(20):4645-55. PubMed PMID: PMC3367872. doi: 10.1182/blood-2011-10-381996
13. Casado C, Galvez C, Pernas M, Tarancon-Diez L, Rodriguez C, Sanchez-Merino V, Vera M, Olivares I, De Pablo-Bernal R, Merino-Mansilla A, Del Romero J, Lorenzo-Redondo R, Ruiz-Mateos E, Salgado M, Martinez-Picado J, Lopez-Galindez C. Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure. Sci Rep. 2020;10(1):1902. PubMed PMID: PMC7002478. doi: 10.1038/s41598-020-58696-y
14. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS pathogens. 2013;9(3):e1003211. PubMed PMID: PMC3597518. doi: 10.1371/journal.ppat.1003211
15. Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, Lawson VA, Crowe S, Maerz A, Sonza S, Learmont J, Sullivan JS, Cunningham A, Dwyer D, Dowton D, Mills J. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science (New York, NY). 1995;270(5238):988-91. PubMed PMID. doi: 10.1126/science.270.5238.988
16. Lobritz MA, Lassen KG, Arts EJ. HIV-1 replicative fitness in elite controllers. Current opinion in HIV and AIDS. 2011;6(3):214-20. PubMed PMID: PMC5730053. doi: 10.1097/COH.0b013e3283454cf5
17. Almeida JR, Price DA, Papagno L, Arkoub ZA, Sauce D, Bornstein E, Asher TE, Samri A, Schnuriger A, Theodorou I, Costagliola D, Rouzioux C, Agut H, Marcelin AG, Douek D, Autran B, Appay V. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. The Journal of experimental medicine. 2007;204(10):2473-85. PubMed PMID: PMC2118466. doi: 10.1084/jem.20070784
18. Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, Van Baarle D, Kostense S, Miedema F, McLaughlin M, Ehler L, Metcalf J, Liu S, Connors M. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nature immunology. 2002;3(11):1061-8. PubMed PMID. doi: 10.1038/ni845
19. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006;107(12):4781-9. PubMed PMID: PMC1895811. doi: 10.1182/blood-2005-12-4818
20. Buggert M, Nguyen S, Salgado-Montes de Oca G, Bengsch B, Darko S, Ransier A, Roberts ER, Del Alcazar D, Brody IB, Vella LA, Beura L, Wijeyesinghe S, Herati RS, Del Rio Estrada PM, Ablanedo-Terrazas Y, Kuri-Cervantes L, Sada Japp A, Manne S, Vartanian S, Huffman A, Sandberg JK, Gostick E, Nadolski G, Silvestri G, Canaday DH, Price DA, Petrovas C, Su LF, Vahedi G, Dori Y, Frank I, Itkin MG, Wherry EJ, Deeks SG, Naji A, Reyes-Teran G, Masopust D, Douek DC, Betts MR. Identification and characterization of HIV-specific resident memory CD8(+) T cells in human lymphoid tissue. Science immunology. 2018;3(24). PubMed PMID. doi: 10.1126/sciimmunol.aar4526
21. Ferre AL, Hunt PW, Critchfield JW, Young DH, Morris MM, Garcia JC, Pollard RB, Yee HF, Jr., Martin JN, Deeks SG, Shacklett BL. Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood. 2009;113(17):3978-89. PubMed PMID: PMC2673124. doi: 10.1182/blood-2008-10-182709
22. Porichis F, Kaufmann DE. HIV-specific CD4 T cells and immune control of viral replication. Current opinion in HIV and AIDS. 2011;6(3):174-80. PubMed PMID: PMC3265969. doi: 10.1097/COH.0b013e3283454058
23. Valdez H, Smith KY, Landay A, Connick E, Kuritzkes DR, Kessler H, Fox L, Spritzler J, Roe J, Lederman MB, Lederman HM, Evans TG, Heath-Chiozzi M, Lederman MM. Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group. AIDS (London, England). 2000;14(1):11-21. PubMed PMID. doi: 10.1097/00002030-200001070-00002
24. Saez-Cirion A, Hamimi C, Bergamaschi A, David A, Versmisse P, Melard A, Boufassa F, Barre-Sinoussi F, Lambotte O, Rouzioux C, Pancino G. Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers. Blood. 2011;118(4):955-64. PubMed PMID: PMC3148172. doi: 10.1182/blood-2010-12-327106
25. O'Connell KA, Han Y, Williams TM, Siliciano RF, Blankson JN. Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. Journal of virology. 2009;83(10):5028-34. PubMed PMID: PMC2682110. doi: 10.1128/jvi.02551-08
26. Ackerman ME, Mikhailova A, Brown EP, Dowell KG, Walker BD, Bailey-Kellogg C, Suscovich TJ, Alter G. Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. PLoS pathogens. 2016;12(1):e1005315. PubMed PMID: PMC4706315. doi: 10.1371/journal.ppat.1005315
27. Gonzalez N, McKee K, Lynch RM, Georgiev IS, Jimenez L, Grau E, Yuste E, Kwong PD, Mascola JR, Alcami J. Characterization of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors. PloS one. 2018;13(3):e0193773. PubMed PMID: PMC5860703. doi: 10.1371/journal.pone.0193773
28. Tarancon-Diez L, Rodriguez-Gallego E, Rull A, Peraire J, Vilades C, Portilla I, Jimenez-Leon MR, Alba V, Herrero P, Leal M, Ruiz-Mateos E, Vidal F. Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection. EBioMedicine. 2019;42:86-96. PubMed PMID: PMC6491381. doi: 10.1016/j.ebiom.2019.03.004
29. Okulicz JF, Marconi VC, Landrum ML, Wegner S, Weintrob A, Ganesan A, Hale B, Crum-Cianflone N, Delmar J, Barthel V, Quinnan G, Agan BK, Dolan MJ. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study. The Journal of infectious diseases. 2009;200(11):1714-23. PubMed PMID. doi: 10.1086/646609
30. Cortes FH, de Paula HHS, Bello G, Ribeiro-Alves M, de Azevedo SSD, Caetano DG, Teixeira SLM, Hoagland B, Grinsztejn B, Veloso VG, Guimaraes ML, Morgado MG. Plasmatic Levels of IL-18, IP-10, and Activated CD8(+) T Cells Are Potential Biomarkers to Identify HIV-1 Elite Controllers With a True Functional Cure Profile. Frontiers in immunology. 2018;9:1576. PubMed PMID: PMC6050358. doi: 10.3389/fimmu.2018.01576
31. Crowell TA, Gebo KA, Blankson JN, Korthuis PT, Yehia BR, Rutstein RM, Moore RD, Sharp V, Nijhawan AE, Mathews WC, Hanau LH, Corales RB, Beil R, Somboonwit C, Edelstein H, Allen SL, Berry SA. Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection. The Journal of infectious diseases. 2015;211(11):1692-702. PubMed PMID: PMC4447832. doi: 10.1093/infdis/jiu809
32. Crowell TA, Ganesan A, Berry SA, Deiss RG, Agan BK, Okulicz JF; Infectious Disease Clinical Research Program (IDCRP) HIV Working Group. Hospitalizations among HIV controllers and persons with medically controlled HIV in the U.S. Military HIV Natural History Study. J Int AIDS Soc. 2016;19(1):20524.
33. Dominguez-Molina B, Leon A, Rodriguez C, Benito JM, Lopez-Galindez C, Garcia F, Del Romero J, Gutierrez F, Viciana P, Alcami J, Leal M, Ruiz-Mateos E. Analysis of Non-AIDS-Defining Events in HIV Controllers. Clin Infect Dis. 2016;62(10):1304-1309.
34. Leon A, Perez I, Ruiz-Mateos E, Benito JM, Leal M, Lopez-Galindez C, Rallon N, Alcami J, Lopez-Aldeguer J, Viciana P, Rodriguez C, Grau E, Iribarren J, Gatell JM, Garcia F. Rate and predictors of progression in elite and viremic HIV-1 controllers. AIDS (London, England). 2016;30(8):1209-20. PubMed PMID. doi: 10.1097/qad.0000000000001050
35. Sajadi MM, Pulijala R, Redfield RR, Talwani R. Chronic immune activation and decreased CD4 cell counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AIDS (London, England). 2012;26(15):1879-84. PubMed PMID: PMC3772623. doi: 10.1097/QAD.0b013e328357f5d1
36. Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, Robinson J, Huang Y, Epling L, Martin JN, Deeks SG, Meinert CL, Van Natta M, Jabs DA, Lederman MM. Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection. J Infect Dis. 2014. PubMed PMID. doi: 10.1093/infdis/jiu238
37. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203. PubMed PMID: PMC2570418. doi: 10.1371/journal.pmed.0050203
38. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, Plants J, Seth A, Wilson CC, Deeks SG, Lederman MM, Landay AL. Soluble markers of inflammation and coagulation, but not T-cell activation, are predictors of non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014. PubMed PMID. doi: 10.1093/infdis/jiu254
39. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, Hsue P, Emu B, Krone M, Lampiris H, Douek D, Martin JN, Deeks SG. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. The Journal of infectious diseases. 2008;197(1):126-33. PubMed PMID: PMC3466592. doi: 10.1086/524143
40. Krishnan S, Wilson EM, Sheikh V, Rupert A, Mendoza D, Yang J, Lempicki R, Migueles SA, Sereti I. Evidence for innate immune system activation in HIV type 1-infected elite controllers. The Journal of infectious diseases. 2014;209(6):931-9. PubMed PMID: PMC3935475. doi: 10.1093/infdis/jit581
41. Li JZ, Arnold KB, Lo J, Dugast AS, Plants J, Ribaudo HJ, Cesa K, Heisey A, Kuritzkes DR, Lauffenburger DA, Alter G, Landay A, Grinspoon S, Pereyra F. Differential levels of soluble inflammatory markers by human immunodeficiency virus controller status and demographics. Open forum infectious diseases. 2015;2(1):ofu117. PubMed PMID: PMC4396431. doi: 10.1093/ofid/ofu117
42. Jacobs ES, Keating SM, Abdel-Mohsen M, Gibb SL, Heitman JW, Inglis HC, Martin JN, Zhang J, Kaidarova Z, Deng X, Wu S, Anastos K, Crystal H, Villacres MC, Young M, Greenblatt RM, Landay AL, Gange SJ, Deeks SG, Golub ET, Pillai SK, Norris PJ. Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression. Journal of virology. 2017;91(6). PubMed PMID: PMC5331794. doi: 10.1128/jvi.02051-16
43. Pereyra F, Lo J, Triant VA, Wei J, Buzon MJ, Fitch KV, Hwang J, Campbell JH, Burdo TH, Williams KC, Abbara S, Grinspoon SK. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS (London, England). 2012;26(18):2409-12. PubMed PMID: PMC3660105. doi: 10.1097/QAD.0b013e32835a9950
44. Hsue PY, Hunt PW, Schnell A, Kalapus SC, Hoh R, Ganz P, Martin JN, Deeks SG. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS. 2009;23(9):1059-67. PubMed PMID: PMC2691772. doi: 10.1097/QAD.0b013e32832b514b
45. Hatano H, Yukl SA, Ferre AL, Graf EH, Somsouk M, Sinclair E, Abdel-Mohsen M, Liegler T, Harvill K, Hoh R, Palmer S, Bacchetti P, Hunt PW, Martin JN, McCune JM, Tracy RP, Busch MP, O'Doherty U, Shacklett BL, Wong JK, Deeks SG. Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS pathogens. 2013;9(10):e1003691. PubMed PMID: PMC3795031. doi: 10.1371/journal.ppat.1003691
46. Li JZ, Segal FP, Bosch RJ, Lalama CM, Roberts-Toler C, Delagreverie H, Getz R, Garcia-Broncano P, Kinslow J, Tressler R, Van Dam CN, Keefer M, Carrington M, Lichterfeld M, Kuritzkes D, Yu XG, Landay A, Sax PE; AIDS Clinical Trials Group Study A5308 Team. ART reduces T cell activation and immune exhaustion markers in HIV controllers. Clin Infect Dis. 2020; 70: 1636-1642
47. Kim CJ, Kovacs C, Chun TW, Kandel G, Osborne BJ, Huibner S, Shahabi K, Yue FY, Benko E, Ostowski M, Kaul R. Antiretroviral therapy in HIV-infected elite controllers: impact on gut immunology, microbial translocation, and biomarkers of serious non-AIDS conditions. Journal of acquired immune deficiency syndromes (1999). 2014;67(5):514-8. PubMed PMID: PMC4231825. doi: 10.1097/qai.0000000000000359
48. Boufassa F, Lechenadec J, Meyer L, Costagliola D, Hunt PW, Pereyra F, Deeks S, Pancino G, Taulera O, Lichterfeld M, Delobel P, Saez-Cirion A, Lambotte O. Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration. PloS one. 2014;9(1):e85516. PubMed PMID: PMC3894966. doi: 10.1371/journal.pone.0085516
49. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease [see comments]. Science. 1997;277(5322):112-6. PubMed PMID. doi: 10.1126/science.277.5322.112
50. Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St Clair M, Kotzin BL, Fox L, Chiozzi MH, Leonard JM, Rousseau F, Wade M, Roe JD, Martinez A, Kessler H. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis. 1998;178(1):70-9. PubMed PMID. doi: 10.1086/515591
51. Bucy RP, Hockett RD, Derdeyn CA, Saag MS, Squires K, Sillers M, Mitsuyasu RT, Kilby JM. Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest. 1999;103(10):1391-8. PubMed PMID: PMC408455. doi: 10.1172/JCI5863
52. Mudd JC, Murphy P, Manion M, Debernardo R, Hardacre J, Ammori J, Hardy GA, Harding CV, Mahabaleshwar GH, Jain MK, Jacobson JM, Brooks AD, Lewis S, Schacker TW, Anderson J, Haddad EK, Cubas RA, Rodriguez B, Sieg SF, Lederman MM. Impaired T cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes. Blood. 2013. PubMed PMID. doi: 10.1182/blood-2012-07-445783
53. Lederman MM, Cannon PM, Currier JS, June CH, Kiem HP, Kuritzkes DR, Lewin SR, Margolis DM, McCune JM, Mellors JW, Schacker TW, Sekaly RP, Tebas P, Walker BD, Douek DC. A Cure for HIV Infection: "Not in My Lifetime" or "Just Around the Corner"? Pathogens & immunity. 2016;1(1):154-64. PubMed PMID: PMC5033048. doi: 10.20411/pai.v1i1.133
54. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295-300. PubMed PMID. doi:
55. Chun TW, Shawn Justement J, Murray D, Kim CJ, Blazkova J, Hallahan CW, Benko E, Costiniuk CT, Kandel G, Ostrowski M, Kaul R, Moir S, Casazza JP, Koup RA, Kovacs C, Fauci AS. Effect of antiretroviral therapy on HIV reservoirs in elite controllers. The Journal of infectious diseases. 2013;208(9):1443-7. PubMed PMID: PMC3789563. doi: 10.1093/infdis/jit306
56. Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane N, Masenya M, Serenata C, Akpomiemie G, Qavi A, Chandiwana N, Norris S, Chersich M, Clayden P, Abrams E, Arulappan N, Vos A, McCann K, Simmons B, Hill A. Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV. N Engl J Med. 2019;381(9):803-15. PubMed PMID. doi: 10.1056/NEJMoa1902824
57. Sax PE, Erlandson KM, Lake JE, McComsey GA, Orkin C, Esser S, Brown TT, Rockstroh JK, Wei X, Carter CC, Zhong L, Brainard DM, Melbourne K, Das M, Stellbrink HJ, Post FA, Waters L, Koethe JR. Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019. PubMed PMID. doi: 10.1093/cid/ciz999
58. Lake JE, Currier JS. Metabolic disease in HIV infection. Lancet Infect Dis. 2013;13(11):964-75. PubMed PMID. doi: 10.1016/s1473-3099(13)70271-8
59. Mouton JP, Cohen K, Maartens G. Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen. Expert Rev Clin Pharmacol. 2016;9(11):1493-503. PubMed PMID. doi: 10.1080/17512433.2016.1221760
60. Chaix ML, Boufassa F, Meyzer C, Leruez-Ville M, Mahjoub N, Nere ML, Genet P, Duvivier C, Lascoux-Combes C, Lambotte O, Ghosn J. Detectable HIV-RNA in semen of HIV controllers. PloS one. 2017;12(8):e0183376. PubMed PMID: PMC5558985. doi: 10.1371/journal.pone.0183376