Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART

PLoS Pathogens

Volumn 7, Issue 2, 2011, Pages

  Graf, Erin H ^a   Mexas, Angela M ^a   Yu, Jianqing J ^a   Shaheen, Farida ^a   Liszewski, Megan K ^a   Di Mascio, Michele ^b   Migueles, Stephen A ^b   Connors, Mark ^b   O'Doherty, Una ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRETROVIRUS AGENT; GAG PROTEIN; SAQUINAVIR; VIRUS DNA; CIRCULAR DNA;

ARTICLE; CD4 LYMPHOCYTE COUNT; CLINICAL ARTICLE; CONTROLLED STUDY; DNA INTEGRATION; ELITE SUPPRESSOR; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFECTION CONTROL; PERIPHERAL BLOOD MONONUCLEAR CELL; VIRUS LOAD; CD4+ T LYMPHOCYTE; COHORT ANALYSIS; GENETICS; HUMAN IMMUNODEFICIENCY VIRUS 1; LONG TERMINAL REPEAT; VIROLOGY; VIRUS DNA CELL DNA INTERACTION;

ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CD4-POSITIVE T-LYMPHOCYTES; COHORT STUDIES; DNA, CIRCULAR; DNA, VIRAL; HIV INFECTIONS; HIV LONG TERMINAL REPEAT; HIV-1; HUMANS; VIRAL LOAD; VIRUS INTEGRATION;

EID: 79952072932     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1001300     Document Type: Article

References (65)

1. Blankson JN, Siliciano RF, (2008) Elite suppression of HIV-1 replication. Immunity 29: 845-847.
2. Lambotte O, Boufassa F, Madec Y, Nguyen A, Goujard C, et al. (2005) HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 41: 1053-1056.
3. Deeks SG, Walker BD, (2007) Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27: 406-416.
4. Blankson JN, (2010) Effector mechanisms in HIV-1 infected elite controllers: highly active immune responses? Antiviral Res 85: 295-302.
5. Migueles SA, Connors M, (2010) Long-term nonprogressive disease among untreated HIV-infected individuals: clinical implications of understanding immune control of HIV. JAMA 304: 194-201.
6. Hubert JB, Burgard M, Dussaix E, Tamalet C, Deveau C, et al. (2000) Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group. AIDS 14: 123-131.
7. Lefrere JJ, Mariotti M, Morand-Joubert L, Thauvin M, Roudot-Thoraval F, (1999) Plasma human immunodeficiency virus RNA below 40 Copies/mL is rare in untreated persons even in the first years of infection. J Infect Dis 180: 526-529.
8. Lassen KG, Lobritz MA, Bailey JR, Johnston S, Nguyen S, et al. (2009) Elite suppressor-derived HIV-1 envelope glycoproteins exhibit reduced entry efficiency and kinetics. PLoS Pathog 5: e1000377.
9. Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, et al. (1999) Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. New Engl J Med 340: 1715-1722.
10. Bailey JR, O'Connell K, Yang HC, Han Y, Xu J, et al. (2008) Transmission of human immunodeficiency virus type 1 from a patient who developed AIDS to an elite suppressor. J Virol 82: 7395-7410.
11. Dinges WL, Richardt J, Friedrich D, Jalbert E, Liu Y, et al. (2010) Virus-specific CD8+ T-cell responses better define HIV disease progression than HLA genotype. J Virol 84: 4461-4468.
12. Migueles SA, Osborne CM, Royce C, Compton AA, Joshi RP, et al. (2008) Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 29: 1009-1021.
13. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, et al. (2008) Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 197: 563-571.
14. Dinoso JB, Kim SY, Siliciano RF, Blankson JN, (2008) A comparison of viral loads between HIV-1-infected elite suppressors and individuals who receive suppressive highly active antiretroviral therapy. Clin Infect Dis 47: 102-104.
15. Blankson JN, Bailey JR, Thayil S, Yang HC, Lassen K, et al. (2007) Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol 81: 2508-2518.
16. Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, et al. (2009) Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 83: 329-335.
17. Julg B, Pereyra F, Buzon MJ, Piechocka-Trocha A, Clark MJ, et al. (2010) Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers. Clin Infect Dis 51: 233-238.
18. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, et al. (2009) The challenge of finding a cure for HIV infection. Science 323: 1304-1307.
19. Chun TW, Engel D, Berrey MM, Shea T, Corey L, et al. (1998) Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A USA 95: 8869-8873.
20. Liszewski MK, Yu JJ, O'Doherty U, (2009) Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods 47: 254-260.
21. Yu JJ, Wu TL, Liszewski MK, Dai J, Swiggard WJ, et al. (2008) A more precise HIV integration assay designed to detect small differences finds lower levels of integrated DNA in HAART treated patients. Virology 379: 78-86.
22. Agosto LM, Liszewski MK, Mexas A, Graf E, Pace M, et al. (2010) Patients on HAART often have an excess of unintegrated HIV DNA: Implications for monitoring reservoirs. Virology 409: 46-53.
23. Rouzioux C, Hubert JB, Burgard M, Deveau C, Goujard C, et al. (2005) Early levels of HIV-1 DNA in peripheral blood mononuclear cells are predictive of disease progression independently of HIV-1 RNA levels and CD4+ T cell counts. J Infect Dis 192: 46-55.
24. Brussel A, Mathez D, Broche-Pierre S, Lancar R, Calvez T, et al. (2003) Longitudinal monitoring of 2-long terminal repeat circles in peripheral blood mononuclear cells from patients with chronic HIV-1 infection. AIDS 17: 645-652.
25. Morlese J, Teo IA, Choi JW, Gazzard B, Shaunak S, (2003) Identification of two mutually exclusive groups after long-term monitoring of HIV DNA 2-LTR circle copy number in patients on HAART. AIDS 17: 679-683.
26. Fischer M, Trkola A, Joos B, Hafner R, Joller H, et al. (2003) Shifts in cell-associated HIV-1 RNA but not in episomal HIV-1 DNA correlate with new cycles of HIV-1 infection in vivo. Antivir Ther 8: 97-104.
27. Buzon M, Massanella M, Libre JM, Esteve A, Dahl V, et al. (2009) HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 16: 460-465.
28. O'Doherty U, Swiggard WJ, Jeyakumar D, McGain D, Malim MH, (2002) A sensitive, quantitative, assay for Human Immunodeficiency Virus type 1 integration. J Virol 76: 10,942-910, 950.
29. Brussel A, Delelis O, Sonigo P, (2005) Alu-LTR real-time nested PCR assay for quantifying integrated HIV-1 DNA. Methods Mol Biol 304: 139-154.
30. Butler SL, Hansen MST, Bushman FD, (2001) A quantitative assay for HIV DNA integration in vivo. Nat Med 7: 631-634.
31. Migueles SA, Weeks KA, Nou E, Berkley AM, Rood JE, et al. (2009) Defective HIV-Specific CD8+ T Cell Polyfunctionality, Proliferation and Cytotoxicity Are Not Restored by Antiretroviral Therapy. J Virol 83: 11876-11889.
32. Svarovskaia ES, Barr R, Zhang X, Pais GC, Marchand C, et al. (2004) Azido-containing diketo acid derivatives inhibit human immunodeficiency virus type 1 integrase in vivo and influence the frequency of deletions at two-long-terminal-repeat-circle junctions. J Virol 78: 3210-3222.
33. Hazuda DJ, Felock P, Witmer M, Wolfe A, Stilmock K, et al. (2000) Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287: 646-650.
34. Engleman A, Bushman FD, Craigie R, (1993) Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex. EMBO J 12: 3269-3275.
35. Ansari-Lari MA, Donehower LA, Gibbs RA, (1995) Analysis of human immunodeficiency virus type 1 integrase mutants. Virology 211: 332-335.
36. Coffin JM, Hughes SH, Varmus HE, (1997) Retroviruses. Cold Spring Harbor, NY Cold Spring Harbor Laboratory Press pp. 171-172.
37. Cara A, Guarnaccia F, Reitz MS, Gallo RC, Lori F, (1995) Self-limiting, cell type-dependent replication of an integrase-defective human immunodeficiency virus type 1 in human primary macrophages but not T lymphocytes. Virology 208: 242-248.
38. Englund G, Theodore TS, Freed EO, Engelman A, Martin MA, (1995) Integration is required for productive infection of monocyte-derived macrophages by Human Immunodeficiency Virus type 1. J Virol 69: 3216-3219.
39. Sakai H, Kawamura M, Sakuragi J, Sakuragi S, Shibata R, et al. (1993) Integration is essential for efficient gene expression of human immunodeficiency virus type 1. J Virol 67: 1169-1174.
40. Stevenson M, Haggerty S, Lamonica CA, Meier CM, Welch SK, et al. (1990) Integration is not necessary for expression of human immunodeficiency virus type 1 protein products. J Virol 64: 2421-2425.
41. Wiskerchen M, Meusing MA, (1995) Identification and characterization of a temperature-sensitive mutant of human immunodeficiency virus type 1 by alanine scanning mutagenesis of the integrase gene. J Virol 69: 597-601.
42. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, et al. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278: 1295-1300.
43. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, et al. (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 9: 727-728.
44. Izopet J, Cazabat M, Pasquier C, Sandres-Saune K, Bonnet E, et al. (2002) Evolution of total and integrated HIV-1 DNA and change in DNA sequences in patients with sustained plasma virus suppression. Virology 302: 393-404.
45. Koelsch KK, Liu L, Haubrich R, May S, Havlir D, et al. (2008) Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis 197: 411-419.
46. Ibanez A, Puig T, Elias J, Clotet B, Ruiz L, et al. (1999) Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients. Aids 13: 1045-1049.
47. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, et al. (2009) HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15: 893-900.
48. O'Connell KA, Brennan TP, Bailey JR, Ray SC, Siliciano RF, et al. (2010) Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus. J Virol 84: 7018-7028.
49. Mens H, Kearney M, Wiegand A, Shao W, Schonning, et al. (2010) HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. J Virol 84: 12971-12981.
50. Sedaghat AR, Rastegar DA, O'Connell KA, Dinoso JB, Wilke CO, et al. (2009) T cell dynamics and the response to HAART in a cohort of HIV-1-infected elite suppressors. Clin Infect Dis 49: 1763-1766.
51. de Quiros JC, Shupert WL, McNeil AC, Gea-Banacloche JC, Flanigan M, et al. (2000) Resistance to replication of human immunodeficiency virus challenge in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors is mediated by CD8(+) T cells and associated with a proliferative response to p24 antigen. J Virol 74: 2023-2028.
52. Rabi SA, O'Connell KA, Nikolaeva D, Bailey JR, Jilek BL, et al. (2010) Unstimulated Primary CD4+ T Cells from HIV Type 1 Positive Elite Suppressors are Fully Susceptible to HIV-1 Entry and Productive Infection. J Virol 85: 979-986.
53. Migueles SA, Laborico AC, Imamichi H, Shupert WL, Royce C, et al. (2003) The differential ability of HLA B*5701+ long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences. J Virol 77: 6889-6898.
54. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al. (2006) HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781-4789.
55. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, et al. (2007) HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A 104: 6776-6781.
56. Saez-Cirion A, Sinet M, Shin SY, Urrutia A, Versmisse P, et al. (2009) Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J Immunol 182: 7828-7837.
57. Hersperger AR, Pereyra F, Nason M, Demers K, Sheth P, et al. (2007) Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog 6: e1000917.
58. Pereyra F, Palmer S, Miura T, Block BL, Wiegand A, et al. (2009) Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis 200: 984-990.
59. Bailey JR, Williams TM, Siliciano RF, Blankson JN, (2006) Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J Exp Med 203: 1357-1369.
60. Bailey JR, Brennan TP, O'Connell KA, Siliciano RF, Blankson JN, (2009) Evidence of CD8+ T-cell-mediated selective pressure on human immunodeficiency virus type 1 nef in HLA-B*57+ elite suppressors. J Virol 83: 88-97.
61. Owen RE, Heitman JW, Hirschkorn DF, Lanteri MC, Biswas HH, et al. (2010) HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses. AIDS 24: 1095-1105.
62. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, et al. (2008) 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 197: 126-133.
63. Chase AJ, Yang HC, Zhang H, Blankson JN, Siliciano RF, (2008) Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation. J Virol 82: 8307-8315.
64. Butler SL, Johnson EP, Bushman FD, (2002) Human Immunodeficiency Virus cDNA Metabolism: Notable Stability of Two-Long Terminal Repeat Circles. Journal of Virology 76: 3739-3747.
65. Agosto LM, Yu JJ, Dai J, Kaletsky R, Monie D, et al. (2007) HIV-1 integrates into resting CD4+ T cells even at low inoculums as demonstrated with an improved assay for HIV-1 integration. Virology 368: 60-72.