Using the Pathogenic and Nonpathogenic Nonhuman Primate Model for Studying Non-AIDS Comorbidities

Current HIV/AIDS Reports

Volumn 12, Issue 1, 2015, Pages 54-67

  Pandrea, Ivona ^a   Landay, Alan ^b   Wilson, Cara ^c   Stock, Jennifer ^d   Tracy, Russell ^e   Apetrei, Cristian ^a  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b RUSH UNIVERSITY MEDICAL CENTER   (United States)

^c UNIVERSITY OF COLORADO   (United States)

^d UNIVERSITY OF PITTSBURGH   (United States)

^e UNIVERSITY OF VERMONT   (United States)

Author keywords

Aging; Chronic inflammation; Chronic obstructive pulmonary disease (COPD); Dysbiosis; HIV associated nephropathy (HIVAN); HIV associated neurocognitive disease (HAND); Human immunodeficiency virus; Hypercoagulation; Microbial translocation; Simian immunodeficiency virus

Indexed keywords

AGING; CARDIOVASCULAR DISEASE; CLINICAL RESEARCH; COMORBIDITY; GASTROINTESTINAL DISEASE; HIV ASSOCIATED DEMENTIA; INFLAMMATION; KIDNEY DISEASE; LIVER DYSFUNCTION; NONHUMAN; OSTEOPENIA; OSTEOPOROSIS; PATHOGENESIS; PRIMATE MODEL; RESPIRATORY TRACT DISEASE; REVIEW; SIMIAN ACQUIRED IMMUNODEFICIENCY SYNDROME; ACQUIRED IMMUNODEFICIENCY SYNDROME; ANIMAL; CARDIOVASCULAR DISEASES; DISEASE MODEL; GASTROINTESTINAL DISEASES; HUMAN; KIDNEY DISEASES; LIVER DISEASES; MACACA; NEUROCOGNITIVE DISORDERS; PATHOGENICITY; PHYSIOLOGY; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; SIMIAN IMMUNODEFICIENCY VIRUS;

ACQUIRED IMMUNODEFICIENCY SYNDROME; AGING; ANIMALS; CARDIOVASCULAR DISEASES; COMORBIDITY; DISEASE MODELS, ANIMAL; GASTROINTESTINAL DISEASES; HUMANS; INFLAMMATION; KIDNEY DISEASES; LIVER DISEASES; MACACA; NEUROCOGNITIVE DISORDERS; OSTEOPOROSIS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; SIMIAN ACQUIRED IMMUNODEFICIENCY SYNDROME; SIMIAN IMMUNODEFICIENCY VIRUS;

EID: 84925494695     PISSN: 15483568     EISSN: 15483576     Source Type: Journal    
DOI: 10.1007/s11904-014-0245-5     Document Type: Review

References (100)

1. Fauci AS, Folkers GK, Dieffenbach CW. HIV-AIDS: much accomplished, much to do. Nat Immunol. 2013;14(11):1104–7. doi:10.1038/ni.2735.
2. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during chronic HIV infection. Immunity. 2013;39(4):633–45. doi:10.1016/j.immuni.2013.10.001. This excellent review discusses the concepts and mechanisms behind the current pathogenesis paradigms of HIV infection and the central role of persistent inflammation in producing non-AIDS comorbidities.
3. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217–26. doi:10.1093/infdis/jir507.
4. Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011;203(6):780–90. doi:10.1093/infdis/jiq118.
5. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, 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(10):1534–43. doi:10.1086/374786.
6. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
7. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol. 2013;119:51–83. doi:10.1016/B978-0-12-407707-2.00002-3. In this paper, the spectrum of non-AIDS comorbidities and malignant complications distinguishable from the opportunistic malignancies traditionally associated with AIDS is grouped in a distinct syndrome that the authors call “residual immune dysregulation syndrome” (RIDS).
8. VandeWoude S, Apetrei C. Going wild: lessons from T-lymphotropic naturally occurring lentiviruses. Clin Microbiol Rev. 2006;19:728–62.
9. Evans DT, Silvestri G. Nonhuman primate models in AIDS research. Curr Opin HIV AIDS. 2013. doi:10.1097/COH.0b013e328361cee8.
10. Lifson JD, Haigwood NL. Lessons in nonhuman primate models for AIDS vaccine research: from minefields to milestones. Cold Spring Harb Perspect Med. 2012;2(6):a007310. doi:10.1101/cshperspect.a007310.
11. Blanco-Melo D, Venkatesh S, Bieniasz PD. Intrinsic cellular defenses against human immunodeficiency viruses. Immunity. 2012;37(3):399–411. doi:10.1016/j.immuni.2012.08.013.
12. Apetrei C, Kaur A, Lerche NW, Metzger M, Pandrea I, Hardcastle J, et al. Molecular epidemiology of SIVsm in US Primate Centers unravels the origin of SIVmac and SIVstm. J Virol. 2005;79(14):8991–9005.
13. Hirsch VM, Dapolito G, Johnson PR, Elkins WR, London WT, Montali RJ, et al. Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J Virol. 1995;69(2):955–67.
14. Mandell DT, Kristoff J, Gaufin T, Gautam R, Ma D, Sandler N, et al. Pathogenic features associated with increased virulence upon simian immunodeficiency virus cross-species transmission from natural hosts. J Virol. 2014;88(12):6778–92. doi:10.1128/JVI. 03785-13.
15. Pandrea I, Gaufin T, Gautam R, Kristoff J, Mandell D, Montefiori D, et al. Functional cure of SIVagm infection in rhesus macaques results in complete recovery of CD4+ T cells and is reverted by CD8+ cell depletion. PLoS Pathog. 2011;7(8):e1002170. doi:10.1371/journal.ppat.1002170.
16. Del Prete GQ, Ailers B, Moldt B, Keele BF, Estes JD, Rodriguez A, et al. Selection of unadapted, pathogenic SHIVs encoding newly transmitted HIV-1 envelope proteins. Cell Host Microbe. 2014;16(3):412–8. doi:10.1016/j.chom.2014.08.003.
17. Hatziioannou T, Del Prete GQ, Keele BF, Estes JD, McNatt MW, Bitzegeio J, et al. HIV-1-induced AIDS in monkeys. Science. 2014;344(6190):1401–5. doi:10.1126/science.1250761.
18. Pandrea I, Apetrei C. Where the wild things are: pathogenesis of SIV infection in African nonhuman primate hosts. Curr HIV/AIDS Rep. 2010;7(1):28–36. doi:10.1007/s11904-009-0034-8.
19. Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med. 2008
20. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narvaez AB, et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood. 2004;104(4):942–7. doi:10.1182/blood-2003-09-3333.
21. Doisne JM, Urrutia A, Lacabaratz-Porret C, Goujard C, Meyer L, Chaix ML, et al. CD8+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection. J Immunol. 2004;173(4):2410–8.
22. Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol. 2012;30:149–73. doi:10.1146/annurev-immunol-020711-075001.
23. Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol. 2006;7(3):235–9.
24. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71. doi:10.1038/nm1511.
25. Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol. 2012;10(9):655–66. doi:10.1038/nrmicro2848.
26. Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest. 2011;121(3):998–1008. doi:10.1172/JCI45157.
27. Klatt NR, Chomont N, Douek DC, Deeks SG. Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol Rev. 2013;254(1):326–42. doi:10.1111/imr.12065.
28. Wijewardana V, Kristoff J, Xu C, Ma D, Haret-Richter G, Stock JL, et al. Kinetics of myeloid dendritic cell trafficking and activation: impact on progressive, nonprogressive and controlled SIV infections. PLoS Pathog. 2013;9(10):e1003600. doi:10.1371/journal.ppat.1003600.
29. Pandrea I, Sodora DL, Silvestri G, Apetrei C. Into the wild: simian immunodeficiency virus (SIV) infection in natural hosts. Trends Immunol. 2008;29(9):419–28.
30. Gordon S, Klatt NR, Milush JM, Engram J, Dunham RM, Paiardini M, et al. Severe depletion of mucosal CD4+ T cells in AIDS-free SIV-infected sooty mangabeys. J Immunol. 2007;179:3026–34.
31. Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, Pattison M, et al. Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol. 2007;179(5):3035–46.
32. Pandrea I, Gaufin T, Brenchley JM, Gautam R, Monjure C, Gautam A, et al. Cutting edge: experimentally induced immune activation in natural hosts of simian immunodeficiency virus induces significant increases in viral replication and CD4+ T cell depletion. J Immunol. 2008;181(10):6687–91.
33. Pandrea I, Cornell E, Wilson C, Ribeiro RM, Ma D, Kristoff J, et al. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood. 2012;120:1357–66. doi:10.1182/blood-2012-03-414706. In this paper, it is reported that cardiovascular disease reported in HIV-infected patients also occurs in pathogenic SIV infection in the absence of ART or of traditional behaviour risk factors. In addition, this paper suggests a link between hypercoagulopathy and microbial translocation.
34. Klatt NR, Harris LD, Vinton CL, Sung H, Briant JA, Tabb B et al. Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection. Mucosal Immunol. 2010:in press. doi:10.1038/mi.2010.14.
35. Klatt NR, Canary LA, Sun X, Vinton CL, Funderburg NT, Morcock DR, et al. Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. J Clin Invest. 2013;123(2):903–7. doi:10.1172/JCI66227. This paper demonstrates that synbiotic treatment (probiotics and prebiotics) results in increased frequency and functionality of gastrointestinal antigen-presenting cells, enhanced reconstitution and functionality of CD4+ T cells, and reduced fibrosis of lymphoid follicles in the colon. As such, synbiotic treatment mitigate inflammatory sequelae.
36. Kristoff J, Haret-Richter G, Ma D, Ribeiro RM, Xu C, Cornell E, et al. Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication. J Clin Invest. 2014;124(6):2802–6. doi:10.1172/JCI75090. In this paper, it is reported the administration of sevelamer that chelate LPS in the gut thus reducing the levels of microbial products translocated into the general circulation may alleviate the levels of systemic inflammation and immune activation and reduce hypercoagulopathy. As such, the paper directly validates the microbial translocation theory and points to interventions that may ameliorate chronic inflammation and prognostic of HIV infection.
37. Pandrea I, Kristoff J, Xu C, Ma D, Stock JL, Ross S et al. Combination antibiotic and antiinflammatory therapy reduces acute inflammation and hypercoagulation in SIV-infected pigtailed macaques. PLoS pathogens. 2015;11(in revision.).
38. High KP, Brennan-Ing M, Clifford DB, Cohen MH, Currier J, Deeks SG, et al. HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Acquir Immune Defic Syndr. 2012;60(1):S1–S18. doi:10.1097/QAI.0b013e31825a3668.
39. Capri M, Salvioli S, Monti D, Caruso C, Candore G, Vasto S, et al. Human longevity within an evolutionary perspective: the peculiar paradigm of a post-reproductive genetics. Exp Gerontol. 2008;43(2):53–60. doi:10.1016/j.exger.2007.06.004.
40. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85. doi:10.1084/jem.20050882.
41. Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev. 2011;10(3):319–29. doi:10.1016/j.arr.2010.11.002.
42. Althoff KN, Justice AC, Gange SJ, Deeks SG, Saag MS, Silverberg MJ, et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS. 2010;24(16):2469–79. doi:10.1097/QAD.0b013e32833e6d14.
43. Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA: J Am Med Assoc. 2012;308(4):387–402. doi:10.1001/jama.2012.7961.
44. Willette AA, Coe CL, Birdsill AC, Bendlin BB, Colman RJ, Alexander AL, et al. Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques. Age. 2013;35(6):2215–27. doi:10.1007/s11357-013-9518-y.
45. Haberthur K, Engelman F, Barron A, Messaoudi I. Immune senescence in aged nonhuman primates. Exp Gerontol. 2010;45(9):655–61. doi:10.1016/j.exger.2010.06.001.
46. Didier ES, Sugimoto C, Bowers LC, Khan IA, Kuroda MJ. Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta). Immun Ageing. 2012;9(1):25. doi:10.1186/1742-4933-9-25.
47. Maniar-Hew K, Clay CC, Postlethwait EM, Evans MJ, Fontaine JH, Miller LA. Innate immune response to LPS in airway epithelium is dependent on chronological age and antecedent exposures. Am J Respir Cell Mol Biol. 2013;49(5):710–20. doi:10.1165/rcmb.2012-0321OC.
48. Josset L, Engelmann F, Haberthur K, Kelly S, Park B, Kawoaka Y, et al. Increased viral loads and exacerbated innate host responses in aged macaques infected with the 2009 pandemic H1N1 influenza A virus. J Virol. 2012;86(20):11115–27. doi:10.1128/JVI. 01571-12.
49. Ma D, Jasinska AJ, Feyertag F, Wijewardana V, Kristoff J, He T, et al. Factors associated with siman immunodeficiency virus transmission in a natural African nonhuman primate host in the wild. J Virol. 2014;88(10):5687–705. doi:10.1128/JVI. 03606-13.
50. Pandrea I, Silvestri G, Apetrei C. AIDS in African nonhuman primate hosts of SIVs: a new paradigm of SIV infection. Curr HIV Res. 2009;6:57–72.
51. Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M, et al. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog. 2010;6(8):e1001052. doi:10.1371/journal.ppat.1001052. This paper demonstrated for the first time that a link can be established between epithelial gut integrity and microbial translocation in SIV-infected macaques.
52. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–84. doi:10.1038/ni.1863.
53. Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 2008;112(7):2826–35.
54. Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, Kasakow Z, et al. Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog. 2009;5(2):e1000295.
55. Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013;5(193):193ra91. doi:10.1126/scitranslmed.3006438.
56. Steele AK, Lee EJ, Vestal B, Hecht D, Dong Z, Rapaport E, et al. Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature. PLoS One. 2014;9(5):e97171. doi:10.1371/journal.pone.0097171.
57. Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK, et al. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol. 2014;7(4):983–94. doi:10.1038/mi.2013.116.
58. Handley SA, Thackray LB, Zhao G, Presti R, Miller AD, Droit L, et al. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell. 2012;151(2):253–66. doi:10.1016/j.cell.2012.09.024. This paper compared the changes in the gut viral communities between pathogenic and nonpathogenic SIV infection and reported that such changes are specifically associated with pathogenic SIV infection. Conversely, no significant change in the gut viral communities could be observed during the nonpathogenic SIV infection in AGMs. As such, the paper provides a mechanistic base for the dysbiosis.
59. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85. doi:10.1038/nm.3145.
60. Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614–22. doi:10.1001/jamainternmed.2013.3728.
61. Justice AC, Freiberg MS, Tracy R, Kuller L, Tate JP, Goetz MB, et al. Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? Clin Infect Dis: Off Pub Infect Dis Soc Am. 2012;54(7):984–94. doi:10.1093/cid/cir989.
62. Pandrea I, Amedee A, Bagby G, Nelson S. Alcohol’s role in HIV transmission and disease progression. Alcohol Res Health. 2010;33:203–18.
63. Gori A, Rizzardini G, Van’t Land B, Amor KB, van Schaik J, Torti C, et al. Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial. Mucosal Immunol. 2011;4(5):554–63. doi:10.1038/mi.2011.15.
64. Byakwaga H, Kelly M, Purcell DF, French MA, Amin J, Lewin SR, et al. Intensification of antiretroviral therapy with raltegravir or addition of hyperimmune bovine colostrum in HIV-infected patients with suboptimal CD4+ T-cell response: a randomized controlled trial. J Infect Dis. 2011;204(10):1532–40. doi:10.1093/infdis/jir559.
65. Sandler NG, Zhang X, Bosch RJ, Funderburg NT, Choi AI, Robinson JK, et al. Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection. J Infect Dis. 2014;210(10):1549–54. doi:10.1093/infdis/jiu305.
66. Pallikkuth S, Micci L, Ende ZS, Iriele RI, Cervasi B, Lawson B, et al. Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL)-21. PLoS Pathog. 2013;9(7):e1003471. doi:10.1371/journal.ppat.1003471.
67. Palella Jr FJ, Phair JP. Cardiovascular disease in HIV infection. Curr Opin HIV AIDS. 2011;6(4):266–71. doi:10.1097/COH.0b013e328347876c.
68. Bissuel F, Berruyer M, Causse X, Dechavanne M, Trepo C. Acquired protein S deficiency: correlation with advanced disease in HIV-1-infected patients. J Acquir Immune Defic Syndr. 1992;5(5):484–9.
69. Shen YM, Frenkel EP. Thrombosis and a hypercoagulable state in HIV-infected patients. Clin Appl Thromb Hemost: Off J Intern Acad Clin Appl Thromb Hemost. 2004;10(3):277–80.
70. Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One. 2012;7(9):e44454. doi:10.1371/journal.pone.0044454.
71. Musselwhite LW, Sheikh V, Norton TD, Rupert A, Porter BO, Penzak SR, et al. Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in HIV. AIDS. 2011;25(6):787–95. doi:10.1097/QAD.0b013e3283453fcb.
72. Calmy A, Gayet-Ageron A, Montecucco F, Nguyen A, Mach F, Burger F, et al. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS. 2009;23(8):929–39.
73. Hatano H, Strain MC, Scherzer R, Bacchetti P, Wentworth D, Hoh R, et al. Increase in 2-long terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with treated HIV infection: a randomized, placebo-controlled trial. J Infect Dis. 2013;208(9):1436–42. doi:10.1093/infdis/jit453.
74. Palella Jr FJ, Gange SJ, Benning L, Jacobson L, Kaplan RC, Landay AL, et al. Inflammatory biomarkers and abacavir use in the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. AIDS. 2010;24(11):1657–65. doi:10.1097/QAD.0b013e3283389dfa.
75. Funderburg NT, Mayne E, Sieg SF, Asaad R, Jiang W, Kalinowska M, et al. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood. 2010;115(2):161–7. doi:10.1182/blood-2009-03-210179.
76. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96.
77. Butt AA, Chang CC, Kuller L, Goetz MB, Leaf D, Rimland D, et al. Risk of heart failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart disease. Arch Intern Med. 2011;171(8):737–43. doi:10.1001/archinternmed.2011.151.
78. Cohen IS, Anderson DW, Virmani R, Reen BM, Macher AM, Sennesh J, et al. Congestive cardiomyopathy in association with the acquired immunodeficiency syndrome. N Engl J Med. 1986;315(10):628–30. doi:10.1056/NEJM198609043151007.
79. De Castro S, D’Amati G, Gallo P, Cartoni D, Santopadre P, Vullo V, et al. Frequency of development of acute global left ventricular dysfunction in human immunodeficiency virus infection. J Am Coll Cardiol. 1994;24(4):1018–24.
80. Lipshultz SE, Chanock S, Sanders SP, Colan SD, Perez-Atayde A, McIntosh K. Cardiovascular manifestations of human immunodeficiency virus infection in infants and children. Am J Cardiol. 1989;63(20):1489–97.
81. Chalifoux LV, Simon MA, Pauley DR, MacKey JJ, Wyand MS, Ringler DJ. Arteriopathy in macaques infected with simian immunodeficiency virus. Lab Investig. 1992;67(3):338–49.
82. Eitner F, Cui Y, Hudkins KL, Schmidt A, Birkebak T, Agy MB, et al. Thrombotic microangiopathy in the HIV-2-infected macaque. Am J Pathol. 1999;155(2):649–61.
83. Shannon RP, Simon MA, Mathier MA, Geng YJ, Mankad S, Lackner AA. Dilated cardiomyopathy associated with simian AIDS in nonhuman primates. Circulation. 2000;101(2):185–93.
84. Yanai T, Lackner AA, Sakai H, Masegi T, Simon MA. Systemic arteriopathy in SIV-infected rhesus macaques (Macaca mulatta). J Med Primatol. 2006;35(2):106–12. doi:10.1111/j.1600-0684.2005.00145.x.
85. Kunisaki KM. Will expanded ART use reduce the burden of HIV-associated chronic lung disease? Curr Opin HIV AIDS. 2014;9:27–33. doi:10.1097/COH.0000000000000018.
86. Assembly. UNG. Political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases. 66th session of the United Nations General Assembly; New York, NY2011. p. September 2011.
87. Kalyesubula R, Wearne N, Semitala FC, Bowa K. HIV-associated renal and genitourinary comorbidities in Africa. J Acquir Immune Defic Syndr. 2014;67 Suppl 1:S68–78. doi:10.1097/QAI.0000000000000259.
88. D’Agati V, Suh JI, Carbone L, Cheng JT, Appel G. Pathology of HIV-associated nephropathy: a detailed morphologic and comparative study. Kidney Int. 1989;35(6):1358–70.
89. Ryom L, Mocroft A, Lundgren JD. Antiretroviral therapy, immune suppression and renal impairment in HIV-positive persons. Curr Opin HIV AIDS. 2014;9(1):41–7. doi:10.1097/COH.0000000000000023.
90. Stephens EB, Tian C, Dalton SB, Gattone 2nd VH. Simian-human immunodeficiency virus-associated nephropathy in macaques. AIDS Res Hum Retrovir. 2000;16(13):1295–306. doi:10.1089/08892220050117050.
91. Clarke CL, Eckhaus MA, Zerfas PM, Elkins WR. Peripheral edema with hypoalbuminemia in a nonhuman primate infected with simian-human immunodeficiency virus: a case report. J Am Assoc Lab Anim Sci: JAALAS. 2008;47(1):42–8.
92. Borda JT, Pauley DR, MacKey JJ, Alvarez X, Simon MA, Klumpp SA. Immunoglobulin-A nephropathy with crescentic glomerulonephritis in a pigtailed macaque (Macaca nemestrina). Vet Pathol. 2004;41(1):44–9. doi:10.1354/vp.41-1-44.
93. Johnson TP, Nath A. New insights into immune reconstitution inflammatory syndrome of the central nervous system. Curr Opin HIV AIDS. 2014;9(6):572–8. doi:10.1097/COH.0000000000000107.
94. Winston A, Vera JH. Can antiretroviral therapy prevent HIV-associated cognitive disorders? Curr Opin HIV AIDS. 2014;9(1):11–6. doi:10.1097/COH.0000000000000016.
95. Williams R, Bokhari S, Silverstein P, Pinson D, Kumar A, Buch S. Nonhuman primate models of NeuroAIDS. J Neurol. 2008;14(4):292–300. doi:10.1080/13550280802074539.
96. Zink MC, Laast VA, Helke KL, Brice AK, Barber SA, Clements JE, et al. From mice to macaques—animal models of HIV nervous system disease. Curr HIV Res. 2006;4(3):293–305.
97. Ali MK, Magee MJ, Dave JA, Ofotokun I, Tungsiripat M, Jones TK, et al. HIV and metabolic, body, and bone disorders: what we know from low- and middle-income countries. J Acquir Immune Defic Syndr. 2014;67 Suppl 1:S27–39. doi:10.1097/QAI.0000000000000256.
98. Mallon PW. Aging with HIV: osteoporosis and fractures. Curr Opin HIV AIDS. 2014;9(4):428–35. doi:10.1097/COH.0000000000000080.
99. Cotter AG, Mallon PW. The effects of untreated and treated HIV infection on bone disease. Curr Opin HIV AIDS. 2014;9(1):17–26. doi:10.1097/COH.0000000000000028.
100. Apetrei C, Pandrea I, Mellors JW. Nonhuman primate models for HIV cure research. PLoS Pathog. 2012;8(8):e1002892. doi:10.1371/journal.ppat.1002892.