Finding a Cure for Human Immunodeficiency Virus-1 Infection

Infectious Disease Clinics of North America

Volumn 28, Issue 4, 2014, Pages 633-650

  Blankson, Joel N ^a   Siliciano, Janet D ^a   Siliciano, Robert F ^a,b  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

Antiretroviral therapy; Cure; HIV; Latent reservoir; Retroviral persistence

Indexed keywords

BRYOSTATIN; CHEMOKINE RECEPTOR CCR5; HLA B27 ANTIGEN; HLA B57 ANTIGEN; PROSTRATIN; PROTEIN KINASE C INHIBITOR; UNCLASSIFIED DRUG; VORINOSTAT; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT;

ACUTE GRANULOCYTIC LEUKEMIA; ALLOGENIC BONE MARROW TRANSPLANTATION; ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; COHORT ANALYSIS; ENZYME ACTIVATION; GENE EXPRESSION; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE RESPONSE; IN VITRO STUDY; NONHUMAN; PERSISTENT VIRUS INFECTION; T LYMPHOCYTE ACTIVATION; TREATMENT OUTCOME; VIRAL CLEARANCE; VIRUS LATENCY; VIRUS REPLICATION; HIV INFECTIONS; IMMUNOLOGY; PHYSIOLOGY; VIROLOGY;

ANTI-HIV AGENTS; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; HIV INFECTIONS; HIV-1; HUMANS; VIRUS LATENCY;

EID: 84913618046     PISSN: 08915520     EISSN: 15579824     Source Type: Journal    
DOI: 10.1016/j.idc.2014.08.007     Document Type: Review

References (114)

1. Sheehy A.M., Gaddis N.C., Choi J.D., et al. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral VIF protein. Nature 2002, 418:646-650.
2. Ho D.D., Neumann A.U., Perelson A.S., et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-126.
3. Wei X., Ghosh S.K., Taylor M.E., et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995, 373:117-122.
4. Piatak M., Saag M.S., Yang L.C., et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993, 259:1749-1754.
5. Rabi S.A., Laird G.M., Durand C.M., et al. Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. JClin Invest 2013, 123:3848-3860.
6. Perelson A.S., Neumann A.U., Markowitz M., et al. HIV-1 dynamics invivo: Virion clearance rate, infected cell life-span, and viral generation time. Science 1996, 271:1582-1586.
7. Doitsh G., Galloway N.L., Geng X., et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 2014, 505:509-514.
8. Walker B.D., Chakrabarti S., Moss B., et al. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature 1987, 328:345-348.
9. Borrow P., Lewicki H., Wei X., et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 1997, 3:205-211.
10. Wong J.K., Strain M.C., Porrata R., et al. Invivo CD8+ T-cell suppression of SIV viremia is not mediated by CTL clearance of productively infected cells. PLoS Pathog 2010, 6:e1000748.
11. Klatt N.R., Shudo E., Ortiz A.M., et al. CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog 2010, 6:e1000747.
12. Perelson A.S., Essunger P., Cao Y., et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997, 387:188-191.
13. Dinoso J.B., Kim S.Y., Wiegand A.M., et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci USA 2009, 106:9403-9408.
14. Chun T.W., Finzi D., Margolick J., et al. Invivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1995, 1:1284-1290.
15. Chun T.W., Carruth L., Finzi D., et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997, 387:183-188.
16. Finzi D., Hermankova M., Pierson T., et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997, 278:1295-1300.
17. Wong J.K., Hezareh M., Gunthard H.F., et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997, 278:1291-1295.
18. Chun T.W., Stuyver L., Mizell S.B., et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997, 94:13193-13197.
19. Finzi D., Blankson J., Siliciano J.D., et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999, 5:512-517.
20. Siliciano J.D., Kajdas J., Finzi D., et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003, 9:727-728.
21. Strain M.C., Gunthard H.F., Havlir D.V., et al. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci USA 2003, 100:4819-4824.
22. Richman D.D., Wrin T., Little S.J., et al. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci USA 2003, 100:4144-4149.
23. Wei X., Decker J.M., Wang S., et al. Antibody neutralization and escape by HIV-1. Nature 2003, 422:307-312.
24. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 1987, 326:711-713.
25. Bohnlein E., Lowenthal J.W., Siekevitz M., et al. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell 1988, 53:827-836.
26. Siliciano J.D., Siliciano R.F. Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol Biol 2005, 304:3-15.
27. Richman D.D., Margolis D.M., Delaney M., et al. The challenge of finding a cure for HIV infection. Science 2009, 323:1304-1307.
28. The International AIDS Society Scientific Working Group on HIV Cure, Deeks S.G., Autran B., et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 2012, 12:607-614.
29. Dieffenbach C.W., Fauci A.S. Thirty years of HIV and AIDS: future challenges and opportunities. Ann Intern Med 2011, 154:766-771.
30. Hutter G., Nowak D., Mossner M., et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. NEngl J Med 2009, 360:692-698.
31. Yukl S.A., Boritz E., Busch M., et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the berlin patient. PLoS Pathog 2013, 9:e1003347.
32. Henrich T.J., Hanhauser E., Sirignano M.N., et al. HIV-1 rebound following allogeneic stem cell transplantation and treatment interruption. Ann Intern Med 2014, 161:319-327.
33. Persaud D., Gay H., Ziemniak C., et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. NEngl J Med 2013, 369:1828-1835.
34. Farber D.L., Yudanin N.A., Restifo N.P. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 2014, 14:24-35.
35. Jilek B.L., Zarr M., Sampah M.E., et al. Aquantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med 2012, 18:446-451.
36. Ghany M.G., Liang T.J. Current and future therapies for hepatitis C virus infection. NEngl J Med 2013, 369:679-680.
37. Sulkowski M.S., Gardiner D.F., Rodriguez-Torres M., et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. NEngl J Med 2014, 370:211-221.
38. Blankson J.N. Control of HIV-1 replication in elite suppressors. Discov Med 2010, 9:261-266.
39. Deeks S.G., Walker B.D. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007, 27:406-416.
40. Okulicz J.F., Lambotte O. Epidemiology and clinical characteristics of elite controllers. Curr Opin HIV AIDS 2011, 6:163-168.
41. Deacon N.J., Tsykin A., Solomon A., et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 1995, 270:988-991.
42. Alexander L., Weiskopf E., Greenough T.C., et al. Unusual polymorphisms in human immunodeficiency virus type 1 associated with nonprogressive infection. JVirol 2000, 74:4361-4376.
43. Blankson J.N., Bailey J.R., Thayil S., et al. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. JVirol 2007, 81:2508-2518.
44. Lamine A., Caumont-Sarcos A., Chaix M.L., et al. Replication-competent HIV strains infect HIV controllers despite undetectable viremia (ANRS EP36 study). AIDS 2007, 21:1043-1045.
45. Julg B., Pereyra F., Buzon M.J., et al. Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers. Clin Infect Dis 2010, 51:233-238.
46. Bailey J.R., O'Connell K., Yang H.C., et al. Transmission of human immunodeficiency virus type 1 from a patient who developed AIDS to an elite suppressor. JVirol 2008, 82:7395-7410.
47. Buckheit R.W., Allen T.G., Alme A., et al. Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs. Nat Commun 2012, 3:716.
48. Bailey J.R., Williams T.M., Siliciano R.F., et al. Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. JExp Med 2006, 203:1357-1369.
49. O'Connell K.A., Brennan T.P., Bailey J.R., et al. Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus. JVirol 2010, 84:7018-7028.
50. Salgado M., Brennan T.P., O'Connell K.A., et al. Evolution of the HIV-1 nef gene in HLA-B*57 positive elite suppressors. Retrovirology 2010, 7:94.
51. Salgado M., Swanson M.D., Pohlmeyer C.W., et al. HLA-B*57 elite suppressor and chronic progressor HIV-1 isolates replicate vigorously and cause CD4+ T cell depletion in humanized BLT mice. JVirol 2014, 88:3340-3352.
52. Migueles S.A., Sabbaghian M.S., Shupert W.L., et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci USA 2000, 97:2709-2714.
53. Pereyra F., Addo M.M., Kaufmann D.E., et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. JInfect Dis 2008, 197:563-571.
54. Lambotte O., Boufassa F., Madec Y., et al. HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 2005, 41:1053-1056.
55. Han Y., Lai J., Barditch-Crovo P., et al. The role of protective HCP5 and HLA-C associated polymorphisms in the control of HIV-1 replication in a subset of elite suppressors. AIDS 2008, 22:541-544.
56. Sajadi M.M., Constantine N.T., Mann D.L., et al. Epidemiologic characteristics and natural history of HIV-1 natural viral suppressors. JAcquir Immune Defic Syndr 2009, 50:403-408.
57. Emu B., Sinclair E., Hatano H., et al. HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control. JVirol 2008, 82:5398-5407.
58. Fellay J., Shianna K.V., Ge D., et al. Awhole-genome association study of major determinants for host control of HIV-1. Science 2007, 317:944-947.
59. International HIV Controllers Study, Pereyra F., Jia X., et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 2010, 330:1551-1557.
60. Betts M.R., Nason M.C., West S.M., et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 2006, 107:4781-4789.
61. Migueles S.A., Osborne C.M., Royce C., et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 2008, 29:1009-1021.
62. Friedrich T.C., Valentine L.E., Yant L.J., et al. Subdominant CD8+ T-cell responses are involved in durable control of AIDS virus replication. JVirol 2007, 81:3465-3476.
63. Rosenberg E.S., Altfeld M., Poon S.H., et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000, 407:523-526.
64. Kaufmann D.E., Lichterfeld M., Altfeld M., et al. Limited durability of viral control following treated acute HIV infection. PLoS Med 2004, 1:e36.
65. Salgado M., Rabi S.A., O'Connell K.A., et al. Prolonged control of replication-competent dual- tropic human immunodeficiency virus-1 following cessation of highly active antiretroviral therapy. Retrovirology 2011, 8:97. 10.1186/1742-4690-8-97.
66. Saez-Cirion A., Bacchus C., Hocqueloux L., et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. PLoS Pathog 2013, 9:e1003211.
67. Chun T.W., Justement J.S., Murray D., et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: Implications for eradication. AIDS 2010, 24:2803-2808.
68. Hunt P.W., 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. JInfect Dis 2008, 197:126-133.
69. Andrade A., Bailey J.R., Xu J., et al. CD4+ T cell depletion in an untreated HIV type 1-infected human leukocyte antigen-B*5801-positive patient with an undetectable viral load. Clin Infect Dis 2008, 46:e78-e82.
70. Krishnan S., Wilson E.M., Sheikh V., et al. Evidence for innate immune system activation in HIV type 1-infected elite controllers. JInfect Dis 2014, 209:931-939.
71. Noel N., Boufassa F., Lecuroux C., et al. Elevated IP10 levels are associated with immune activation and low CD4(+) T-cell counts in HIV controller patients. AIDS 2014, 28:467-476.
72. Davey R.T., Bhat N., Yoder C., et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA 1999, 96:15109-15114.
73. Joos B., Fischer M., Kuster H., et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci USA 2008, 105:16725-16730.
74. Cooper A., Garcia M., Petrovas C., et al. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature 2013, 498:376-379.
75. Shan L., Deng K., Shroff N.S., et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 2012, 36:491-501.
76. Denton P.W., Long J.M., Wietgrefe S.W., et al. Targeted cytotoxic therapy kills persisting HIV infected cells during ART. PLoS Pathog 2014, 10:e1003872.
77. Chun T.W., Engel D., Mizell S.B., et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med 1999, 5:651-655.
78. Prins J.M., Jurriaans S., van Praag R.M., et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 1999, 13:2405-2410.
79. Kulkosky J., Nunnari G., Otero M., et al. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. JInfect Dis 2002, 186:1403-1411.
80. Jordan A., Bisgrove D., Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells invitro. EMBO J 2003, 22:1868-1877.
81. Sahu G.K., Lee K., Ji J., et al. Anovel invitro system to generate and study latently HIV-infected long-lived normal CD4+ T-lymphocytes. Virology 2006, 355:127-137.
82. Burke B., Brown H.J., Marsden M.D., et al. Primary cell model for activation-inducible human immunodeficiency virus. JVirol 2007, 81:7424-7434.
83. Spina C.A., Anderson J., Archin N.M., et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog 2013, 9:e1003834.
84. Xing S., Siliciano R.F. Targeting HIV latency: Pharmacologic strategies toward eradication. Drug Discov Today 2013, 18:541-551.
85. Van Lint C., Emiliani S., Ott M., et al. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J 1996, 15:1112-1120.
86. He G., Ylisastigui L., Margolis D.M. The regulation of HIV-1 gene expression: The emerging role of chromatin. DNA Cell Biol 2002, 21:697-705.
87. Ylisastigui L., Archin N.M., Lehrman G., et al. Coaxing HIV-1 from resting CD4 T cells: Histone deacetylase inhibition allows latent viral expression. AIDS 2004, 18:1101-1108.
88. Archin N.M., Espeseth A., Parker D., et al. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses 2009, 25:207-212.
89. Archin N.M., Liberty A.L., Kashuba A.D., et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 2012, 487:482-485.
90. Archin N.M., Bateson R., Tripathy M., et al. HIV-1 expression within resting CD4 T-cells following multiple doses of vorinostat. JInfect Dis 2014, 210:728-735.
91. Blazkova J., Chun T.W., Belay B.W., et al. Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy. JInfect Dis 2012, 206:765-769.
92. Bullen C.K., Laird G.M., Durand C.M., et al. New exvivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency invivo. Nat Med 2014, 20(4):425-429.
93. Contreras X., Schweneker M., Chen C.S., et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. JBiol Chem 2009, 284:6782-6789.
94. Kulkosky J., Culnan D.M., Roman J., et al. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 2001, 98:3006-3015.
95. Korin Y.D., Brooks D.G., Brown S., et al. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. JVirol 2002, 76:8118-8123.
96. Brooks D.G., Hamer D.H., Arlen P.A., et al. Molecular characterization, reactivation, and depletion of latent HIV. Immunity 2003, 19:413-423.
97. Williams S.A., Chen L.F., Kwon H., et al. Prostratin antagonizes HIV latency by activating NF-kappaB. JBiol Chem 2004, 279:42008-42017.
98. Beans E.J., Fournogerakis D., Gauntlett C., et al. Highly potent, synthetically accessible prostratin analogs induce latent HIV expression invitro and exvivo. Proc Natl Acad Sci USA 2013, 110:11698-11703.
99. Didigu C.A., Wilen C.B., Wang J., et al. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood 2014, 123:61-69.
100. Ye L., Wang J., Beyer A.I., et al. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Delta32 mutation confers resistance to HIV infection. Proc Natl Acad Sci USA 2014, 111:9591-9596.
101. Hansen S.G., Piatak M., Ventura A.B., et al. Immune clearance of highly pathogenic SIV infection. Nature 2013, 502:100-104.
102. Dornadula G., Zhang H., VanUitert B., et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA 1999, 282:1627-1632.
103. Palmer S., Wiegand A.P., Maldarelli F., et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. JClin Microbiol 2003, 41:4531-4536.
104. Maldarelli F., Palmer S., King M.S., et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 2007, 3:e46.
105. Palmer S., Maldarelli F., Wiegand A., et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA 2008, 105:3879-3884.
106. O'Doherty U., Swiggard W.J., Jeyakumar D., et al. Asensitive, quantitative assay for human immunodeficiency virus type 1 integration. JVirol 2002, 76:10942-10950.
107. Yu J.J., Wu T.L., Liszewski M.K., et al. Amore precise HIV integration assay designed to detect small differences finds lower levels of integrated DNA in HAART treated patients. Virology 2008, 379:78-86.
108. Strain M.C., Richman D.D. New assays for monitoring residual HIV burden in effectively treated individuals. Curr Opin HIV AIDS 2013, 8:106-110.
109. Eriksson S., Graf E.H., Dahl V., et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog 2013, 9:e1003174.
110. Ho Y.C., Shan L., Hosmane N.N., et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 2013, 155:540-551.
111. Harris R.S., Bishop K.N., Sheehy A.M., et al. DNA deamination mediates innate immunity to retroviral infection. Cell 2003, 113:803-809.
112. Nakagawa F., May M., Phillips A. Life expectancy living with HIV: Recent estimates and future implications. Curr Opin Infect Dis 2013, 26:17-25.
113. Johnson L.F., Mossong J., Dorrington R.E., et al. Life expectancies of south African adults starting antiretroviral treatment: Collaborative analysis of cohort studies. PLoS Med 2013, 10:e1001418.
114. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2013. Available at: http://Aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.