Disease-modifying therapeutic concepts for HIV in the era of highly active antiretroviral therapy

Journal of Acquired Immune Deficiency Syndromes

Volumn 58, Issue 3, 2011, Pages 297-303

  Butler, Scott L ^a   Valdez, Hernan ^b   Westby, Michael ^a   Perros, Manos ^c   June, Carl H ^d   Jacobson, Jeffrey M ^e   Levy, Yves ^f   Cooper, David A ^g   Douek, Daniel ^h   Lederman, Michael M ⁱ   Tebas, Pablo ^d  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^b PFIZER INC   (United States)

^c ASTRAZENECA   (United Kingdom)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

^e DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

^f UNIVERSITÉ PARIS EST CRÉTEIL   (France)

^g UNIVERSITY OF NEW SOUTH WALES   (Australia)

^h NATIONAL INSTITUTES OF HEALTH   (United States)

ⁱ UNIVERSITY HOSPITALS OF CLEVELAND   (United States)

Author keywords

clinical trials; disease modifying therapy; genetic therapy; HIV infection; immune activation; microbial translocation; proof of concept

Indexed keywords

CHEMOKINE RECEPTOR CCR5; INTERLEUKIN 7; MARAVIROC; RECOMBINANT INTERLEUKIN 2;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; BACTERIAL TRANSLOCATION; CD4 LYMPHOCYTE COUNT; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL RENEWAL; CHRONIC DISEASE; DISEASE COURSE; FIBROSIS; GENE THERAPY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE ACTIVATION; IMMUNE RESPONSE; LYMPHOCYTE DEPLETION; MIXED INFECTION; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION; TARGET CELL; VIRUS REPLICATION;

EID: 80054962584     PISSN: 15254135     EISSN: 10779450     Source Type: Journal    
DOI: 10.1097/QAI.0b013e31822ccfcc     Document Type: Review

References (102)

1. Kaufmann GR, Zaunders JJ, Cunningham P, et al. Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection. AIDS. 2000;14:2643-2651. (Pubitemid 32118717)
2. Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet. 2007;370:407-413. (Pubitemid 47176633)
3. Moore RD, Keruly JC, Gebo KA, et al. An improvement in virologic response to highly active antiretroviral therapy in clinical practice from 1996 through 2002. J Acquir Immune Defic Syndr. 2005;39:195-198. (Pubitemid 40741118)
4. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis. 2009;48:350-361.
5. Valdez H, Connick E, Smith KY, et al. Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease. AIDS. 2002;16:1859-1866.
6. Liu Z, Cumberland WG, Hultin LE, et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:332-340. (Pubitemid 28359882)
7. Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179:859-870. (Pubitemid 29159331)
8. Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003;17:1881-1888. (Pubitemid 37070273)
9. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:E203.
10. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. 2009;200:973-983.
11. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44:441-446. (Pubitemid 46147630)
12. Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48:787-794.
13. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46:72-77. (Pubitemid 47514615)
14. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22: 841-848. (Pubitemid 351563833)
15. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22:2409-2418.
16. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632-1641 (Pubitemid 44232373)
17. van Lelyveld S, Gras L, Kesselring A, et al. Incomplete immune recovery on HAART is associated with significantly more cardiovascular events and a trend towards more non-AIDS-related malignancies in Dutch ATHENA cohort In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
18. Silverberg M, Xu L, Chao C, et al. Immunodeficiency, HIV RNA levels, and risk of non-AIDS-defining cancers In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
19. Smith C, Sabin CA, Lundgren JD, et al. and The D:A:D Study Group. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D study. AIDS. 2010;24:1537-1548.
20. Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007; 146:87-95. (Pubitemid 351640011)
21. Lewden C, Salmon D, Morlat P, et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol. 2005;34:121-130. (Pubitemid 40347381)
22. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trial Group protocol 384. Clin Infect Dis. 2009;48:350-361.
23. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010; 363:257-265.
24. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis. 2010;50:1512-1520.
25. Smit C, Hallett TB, Lange J, et al. Late entry to HIV care limits the impact of anti-retroviral therapy in the Netherlands. PLoS One. 2008;3:e1949.
26. Giorgi JV, Liu Z, Hultin LE, et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: Results of 6 years of follow-up. J Acquir Immune Defic Syndr. 1993;6:904-912. (Pubitemid 23207458)
27. Lin RY, Nygren EJ, Valinsky JE, et al. T cell immunophenotypes and DR antigen expression in intravenous drug users: relationship to human immunodeficiency virus serology. Arch Allergy Appl Immunol. 1988; 87:263-268. (Pubitemid 19010884)
28. Sachsenberg N, Perelson AS, Yerly S, et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by ki-67 antigen. J Exp Med. 1998;187:1295-1303. (Pubitemid 28189118)
29. Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983;309:453-458. (Pubitemid 13041485)
30. Hellerstein M, Hanley MB, Cesar D, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med. 1999;5:83-89. (Pubitemid 29051003)
31. Hazenberg MD, Hamann D, Schuitemaker H, et al. T cell depletion in HIV-1 infection: How CD4+ T cells go out of stock. Nat Immunol. 2000;1:285-289.
32. Valdez H, Lederman MM. Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev. 1997 187-228.
33. Neuhaus J, Jacobs DR, Jr., Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010;201:1788-1795.
34. Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200:749-759. (Pubitemid 39299461)
35. Estes J, Baker JV, Brenchley JM, et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis. 2008;198:456-464.
36. Schacker TW, Brenchley JM, Beilman GJ, et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol. 2006;13:556-560. (Pubitemid 43736456)
37. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187:1534-1543. (Pubitemid 36578959)
38. Fleury S, Rizzardi GP, Chapuis A, et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc Natl Acad Sci USA. 2000;97:5393-5398. (Pubitemid 30313729)
39. Hunt PW, Brenchley J, Sinclair E, et al. 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. J Infect Dis. 2008;197:126-133. (Pubitemid 351263476)
40. Gandhi RT, Spritzler J, Chan E, et al. Effect of baseline-and treatmentrelated factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: Results from ACTG 384. J Acquir Immune Defic Syndr. 2006;42:426-434. (Pubitemid 44050889)
41. Anthony KB, Yoder C, Metcalf JA, et al. Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover. J Acquir Immune Defic Syndr. 2003;33:125-133. (Pubitemid 36793144)
42. Peters L. INSIGHT SMART Study Group Biomarkers of inflammation and coagulation and risk of non-AIDS death in HIV/hepatitis coinfected patients in the SMART study In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
43. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51:268-273.
44. Hsue PY, Hunt P, Schnell A, et al. Rapid progression of atherosclerosis at the carotid bifurcation is linked to inflammation in HIV-infected patients In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
45. Ross AC, Rizk N, O'Riordan MA, et al. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2009;49:1119-1127.
46. Lau B, Sharrett AR, Kingsley LA, et al. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med. 2006;166:64-70. (Pubitemid 43063843)
47. Buzón MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16:460-465.
48. Kolber MA, Saenz MO, Tanner TJ, et al. Intensification of a suppressive HAART regimen increases CD4 counts and decreases CD8+ T-cell activation. Clin Immunol. 2008;126:315-321. (Pubitemid 351221429)
49. Yukl SA, Shergill AK, McQuaid K, et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010;24:2451-2460.
50. Hatano H, Hayes TL, Dahl V, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2011;203: 960-968.
51. Gandhi RT, Zheng L, Bosch RJ, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: A randomized controlled trial. PLoS Med. 2010;7:e1000321.
52. Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG5256 In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
53. Gutierrez C, Diaz L, Hernandez-Nova B, et al. Effect of the intensification with CCR5 antagonist on the decay of the HIV-1 latent reservoir and residual viremia In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
54. Wilkin TJ, Ribaudo HR, Tenorio AR, et al. The relationship of CCR5 antagonists to CD4+ T-cell gain: A meta-regression of recent clinical trials in treatment-experienced HIV-infected patients. HIV Clin Trials. 2010;11:351-358.
55. Asmuth DM, Goodrich J, Cooper DA, et al. CD4+ T-cell restoration after 48 weeks in the maraviroc treatment-experienced trials MOTIVATE 1 and 2. J Acquir Immune Defic Syndr. 2010;54:394-397.
56. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201:803-813.
57. Saag M, Goodrich J, Fatkenheuer G, et al. A double-blind, placebocontrolled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis. 2009;199:1638-1647.
58. Funderburg N, Kalinowska M, Eason J, et al. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and their association with CD4 cell rises in HIV-infected patients. PLoS One. 2010;5:e13188.
59. Hernandez-Novoa B, Madrid N, Vallejo A, et al. Assessment of residual HIV-1 viremia and persistent viral replication in highly suppressed patients: comparison of direct and indirect methods In: Proceedings from the XVIII International AIDS Conference; July 18-23, 2010; Vienna, Austria.
60. Hunt P, Shulman N, Hayes T, et al. Immunomodulatory effects of MVC intensification in HIV-infected individuals with incomplete CD4+ T cell recovery during suppressive ART In: Proceedings from the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, MA.
61. Sankaran S, George MD, Reay E, et al. Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration. J Virol. 2008:538-545. (Pubitemid 350309168)
62. Li Q, Estes JD, Duan L, et al. Simian immunodeficiency virus-induced intestinal cell apoptosis is the underlying mechanism of the regenerative enteropathy of early infection. J Infect Dis. 2008;197:420-429. (Pubitemid 351263424)
63. El Hed A, Khaitan A, Kozhaya L, et al. Susceptibility of human Th17 cells to human immunodeficiency virus and their perturbation during infection. J Infect Dis. 2010;201:843-854.
64. Cecchinato V, Trindade CJ, Laurence A, et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 2008;1:279-288. (Pubitemid 351850534)
65. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365-1371. (Pubitemid 44924494)
66. Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis. 2009;199:1177-1185.
67. Floren CH, Chinenye S, Elfstrand L, et al. ColoPlus, a new product based on bovine colostrum, alleviates HIV-associated diarrhoea. Scand J Gastroenterol. 2006;41:682-686. (Pubitemid 43995009)
68. Veldhoen M, Hirota K, Christensen J, et al. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med. 2009;206:43-49.
69. Sun PP, Perianayagam MC, Jaber BL. Endotoxin-binding affinity of sevelamer: a potential novel anti-inflammatory mechanism. Kidney Int. 2009;76:S20-S25.
70. Funderburg N, Luciano AA, Jiang W, et al. Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis. PLoS One. 2008;3:e1915.
71. Piconi S, Parisotto S, Rizzardini G, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, ART-treated, immunological non-responders. Blood. 2011 [published online ahead of print May 16, 2011] doi:10.1182/blood-2011-01-329060.
72. Naeger DM, Martin JN, Sinclair E, et al. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One. 2010;5:e8886.
73. Hunt PW, Martin JN, Sinclair E, et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203:1474-1483.
74. Mehandru S, Poles MA, Tenner-Racz K, et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 2006;3:e484.
75. Schacker TW, Reilly C, Beilman GJ, et al. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS. 2005;19:2169-2171. (Pubitemid 41669008)
76. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials. Lancet. 2011;377:1760-1769.
77. Brenchley JM, Douek DC. The mucosal barrier and immune activation in HIV pathogenesis. Curr Opin HIV AIDS. 2008;3:356-361. (Pubitemid 351521021)
78. Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of crohn's disease: a meta-analysis. Clin Gastroenterol Hepatol. 2009;7:874-881.
79. Dinarello CA. Anti-cytokine therapeutics and infections. Vaccine. 2003; 21(suppl 2):S24-S34. (Pubitemid 36603315)
80. Centers for Disease Control and Prevention (CDC). Tuberculosis associated with blocking agents against tumor necrosis factor-alpha-California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2004;53:683-686.
81. deRoda Husman AM, Blaak H, Brouwer M, et al. CC chemokine receptor 5 cell-surface expression in relation to CC chemokine receptor 5 genotype and the clinical course of HIV infection. J Immunol. 1999; 163:4597-4603. (Pubitemid 29474531)
82. Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722-725.
83. Novembre J, Galvani AP, Slatkin M. The geographic spread of the CCR5 Delta32 HIV-resistance allele. PLoS Biol. 2005;3:e399.
84. Anderson JS, Walker J, Nolta JA, et al. Specific transduction of HIVsusceptible cells for CCR5 knockdown and resistance to HIV infection: A novel method for targeted gene therapy and intracellular immunization. J Acquir Immune Defic Syndr. 2009;52:152-161.
85. Holt N, Wang J, Kim K, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010;28:839-847.
86. Perez EE, Wang J, Miller JC, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26:808-816. (Pubitemid 351961450)
87. Mitsuyasu RT, Merigan TC, Carr A, et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med. 2009;15:285-292.
88. Levine BL, Humeau LM, Boyer J, et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA. 2006;103:17372-17377. (Pubitemid 44788976)
89. Tebas P, Stein D, Zifchak L, et al. Prolonged control of viremia after transfer of autologous CD4 T cells genetically modified with a lentiviral vector expressing long antisense to HIV env (VRX496) In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
90. Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009; 360:692-698.
91. Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood. 2011;117:2791-2799.
92. Abrams D, Lévy Y, Losso MH, et al. INSIGHT-ESPRIT Study Group, SILCAAT Scientific Committee. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361:1548-1559.
93. Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009;119:997-1007.
94. Sereti I, Dunham RM, Spritzler J, et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood. 2009;113: 6304-6314.
95. Weiss L, Letimier FA, Carriere M, et al. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients. Proc Natl Acad Sci USA. 2010;107: 10632-10637.
96. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Rockville, MD: Department of Health and Human Services; 2011:1-166.
97. Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352-1363.
98. Guiguet M, Porter K, Phillips A, et al. Clinical progression rates by CD4 cell category before and after the initiation of combination antiretroviral therapy (cART). Open AIDS J. 2008;2:3-9.
99. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J InfectDis. 2008;197:1133-1144. (Pubitemid 351590049)
100. Lehrman G, Hogue IB, Palmer S, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005;366:549-555. (Pubitemid 41140329)
101. Margolis DM. Eradication therapies for HIV infection: time to begin again. AIDS Res Hum Retroviruses. 2011;27:347-353.
102. Carter CC, Onafuwa-Nuga A, McNamara LA, et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010;16:446-451