Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop
Article Sidebar
Main Article Content
Abstract
People with HIV (PWH) experience accentuated biological aging, as defined
by markers of inflammation, immune dysfunction, and the epigenetic clock.
They also have an elevated risk of multiple age-associated comorbidities.
To discuss current knowledge, research gaps, and priorities in aging and
age-related comorbidities in treated HIV infection, the NIH program staff
organized a workshop held in Bethesda, Maryland in September 2019. This
review article describes highlights of discussions led by the
Pathogenesis/Basic Science Research working group that focused on three
high priority topics: immunopathogenesis; the microbiome/virome; and aging
and senescence. We summarize knowledge in these fields and describe key
questions for research on the pathogenesis of aging and age-related
comorbidities in PWH. Understanding the drivers and mechanisms underlying
accentuated biological aging is a high priority that will help identify
potential therapeutic targets to improve healthspan in older PWH.
Downloads
Article Details
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. Schouten J, Wit FW, Stolte IG, Kootstra NA, van der Valk M, Geerlings SE, Prins M, Reiss P, Group AGCS. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis. 2014;59(12):1787-97. PubMed PMID. doi: 10.1093/cid/ciu701
2. Hawkins KL, Brown TT, Margolick JB, Erlandson KM. Geriatric syndromes: new frontiers in HIV and sarcopenia. AIDS. 2017;31 Suppl 2:S137-S46. PubMed PMID: PMC5693390. doi: 10.1097/QAD.0000000000001444
3. De Francesco D, Sabin CA, Reiss P. Multimorbidity patterns in people with HIV. Curr Opin HIV AIDS. 2019. PubMed PMID. doi: 10.1097/COH.0000000000000595
4. Bowman E, Funderburg NT. Lipidome Abnormalities and Cardiovascular Disease Risk in HIV Infection. Curr HIV/AIDS Rep. 2019;16(3):214-23. PubMed PMID: PMC6579629. doi: 10.1007/s11904-019-00442-9
5. De Francesco D, Wit FW, Burkle A, Oehlke S, Kootstra NA, Winston A, Franceschi C, Garagnani P, Pirazzini C, Libert C, Grune T, Weber D, Jansen E, Sabin CA, Reiss P, the Co-morBidity in Relation to AC. Do people living with HIV experience greater age advancement than their HIV-negative counterparts? AIDS. 2019;33(2):259-68. PubMed PMID: PMC6319574. doi: 10.1097/QAD.0000000000002063
6. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, Group CT. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-31. PubMed PMID. doi: 10.1056/NEJMoa1707914
7. Pandrea I, Cornell E, Wilson C, Ribeiro RM, Ma D, Kristoff J, Xu C, Haret-Richter GS, Trichel A, Apetrei C, Landay A, Tracy R. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood. 2012;120(7):1357-66. PubMed PMID: PMC3423778. doi: 10.1182/blood-2012-03-414706
8. Margolick JB, Bream JH, Martinez-Maza O, Lopez J, Li X, Phair JP, Koletar SL, Jacobson LP. Frailty and Circulating Markers of Inflammation in HIV+ and HIV- Men in the Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 2017;74(4):407-17. PubMed PMID: PMC5365031. doi: 10.1097/QAI.0000000000001261
9. Erlandson KM, Allshouse AA, Jankowski CM, Lee EJ, Rufner KM, Palmer BE, Wilson CC, MaWhinney S, Kohrt WM, Campbell TB. Association of functional impairment with inflammation and immune activation in HIV type 1-infected adults receiving effective antiretroviral therapy. J Infect Dis. 2013;208(2):249-59. PubMed PMID: PMC3685225. doi: 10.1093/infdis/jit147
10. Desquilbet L, Jacobson LP, Fried LP, Phair JP, Jamieson BD, Holloway M, Margolick JB, Multicenter ACS. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62(11):1279-86. PubMed PMID. doi: 10.1093/gerona/62.11.1279
11. Helleberg M, Afzal S, Kronborg G, Larsen CS, Pedersen G, Pedersen C, Gerstoft J, Nordestgaard BG, Obel N. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis. 2013;56(5):727-34. PubMed PMID. doi: 10.1093/cid/cis933
12. Ikeda ML, Barcellos NT, Alencastro PR, Wolff FH, Moreira LB, Gus M, Brandao AB, Fuchs FD, Fuchs SC. Alcohol Drinking Pattern: A Comparison between HIV-Infected Patients and Individuals from the General Population. PLoS One. 2016;11(6):e0158535. PubMed PMID: PMC4928875. doi: 10.1371/journal.pone.0158535
13. Garin N, Velasco C, De Pourcq JT, Lopez B, Gutierrez Mdel M, Haro JM, Feliu A, Mangues MA, Trilla A. Recreational drug use among individuals living with HIV in Europe: review of the prevalence, comparison with the general population and HIV guidelines recommendations. Front Microbiol. 2015;6:690. PubMed PMID: PMC4500990. doi: 10.3389/fmicb.2015.00690
14. Castro JG, Alcaide ML. High Rates of STIs in HIV-Infected Patients Attending an STI Clinic. South Med J. 2016;109(1):1-4. PubMed PMID: PMC4705853. doi: 10.14423/SMJ.0000000000000389
15. Scully EP. Sex Differences in HIV Infection: Mystique Versus Machismo. Pathog Immun. 2018;3(1):82-113. PubMed PMID: PMC6103226. doi: 10.20411/pai.v3i1.238
16. Hackler E, 3rd, Lew J, Gore MO, Ayers CR, Atzler D, Khera A, Rohatgi A, Lewis A, Neeland I, Omland T, de Lemos JA. Racial Differences in Cardiovascular Biomarkers in the General Population. J Am Heart Assoc. 2019;8(18):e012729. PubMed PMID: PMC6817997. doi: 10.1161/JAHA.119.012729
17. Kityo C, Makamdop KN, Rothenberger M, Chipman JG, Hoskuldsson T, Beilman GJ, Grzywacz B, Mugyenyi P, Ssali F, Akondy RS, Anderson J, Schmidt TE, Reimann T, Callisto SP, Schoephoerster J, Schuster J, Muloma P, Ssengendo P, Moysi E, Petrovas C, Lanciotti R, Zhang L, Arevalo MT, Rodriguez B, Ross TM, Trautmann L, Sekaly RP, Lederman MM, Koup RA, Ahmed R, Reilly C, Douek DC, Schacker TW. Lymphoid tissue fibrosis is associated with impaired vaccine responses. J Clin Invest. 2018;128(7):2763-73. PubMed PMID: PMC6025977. doi: 10.1172/JCI97377
18. Hunt PW, Lee SA, Siedner MJ. Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection. J Infect Dis. 2016;214 Suppl 2:S44-50. PubMed PMID: PMC5021241. doi: 10.1093/infdis/jiw275
19. Kulkarni M, Bowman E, Gabriel J, Amburgy T, Mayne E, Zidar DA, Maierhofer C, Turner AN, Bazan JA, Koletar SL, Lederman MM, Sieg SF, Funderburg NT. Altered Monocyte and Endothelial Cell Adhesion Molecule Expression Is Linked to Vascular Inflammation in Human Immunodeficiency Virus Infection. Open Forum Infect Dis. 2016;3(4):ofw224. PubMed PMID: PMC5198584. doi: 10.1093/ofid/ofw224
20. Bowman ER, Kulkarni M, Gabriel J, Cichon MJ, Riedl K, Belury MA, Lake JE, Richardson B, Cameron C, Cameron M, Koletar SL, Lederman MM, Sieg SF, Funderburg NT. Altered Lipidome Composition Is Related to Markers of Monocyte and Immune Activation in Antiretroviral Therapy Treated Human Immunodeficiency Virus (HIV) Infection and in Uninfected Persons. Front Immunol. 2019;10:785. PubMed PMID: PMC6477036. doi: 10.3389/fimmu.2019.00785
21. D’Antoni ML, Mitchell BI, McCurdy S, Byron MM, Ogata-Arakaki D, Chow D, Mehta NN, Boisvert WA, Lefebvre E, Shikuma CM, Ndhlovu LC, Baumer Y. Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression. J Leukoc Biol. 2018;104(6):1241-52. PubMed PMID: PMC6258344. doi: 10.1002/JLB.5A0817-328RRR
22. Desquilbet L, Margolick JB, Fried LP, Phair JP, Jamieson BD, Holloway M, Jacobson LP, Multicenter ACS. Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men. J Acquir Immune Defic Syndr. 2009;50(3):299-306. PubMed PMID: PMC2699396. doi: 10.1097/QAI.0b013e3181945eb0
23. Duffau P, Ozanne A, Bonnet F, Lazaro E, Cazanave C, Blanco P, Riviere E, Desclaux A, Hyernard C, Gensous N, Pellegrin I, Wittkop L. Multimorbidity, age-related comorbidities and mortality: association of activation, senescence and inflammation markers in HIV adults. AIDS. 2018;32(12):1651-60. PubMed PMID. doi: 10.1097/QAD.0000000000001875
24. Erlandson KM, Ng DK, Jacobson LP, Margolick JB, Dobs AS, Palella FJ, Jr., Lake JE, Bui H, Kingsley L, Brown TT. Inflammation, Immune Activation, Immunosenescence, and Hormonal Biomarkers in the Frailty-Related Phenotype of Men With or at Risk for HIV Infection. J Infect Dis. 2017;215(2):228-37. PubMed PMID: PMC5897840. doi: 10.1093/infdis/jiw523
25. Funderburg NT, Zidar DA, Shive C, Lioi A, Mudd J, Musselwhite LW, Simon DI, Costa MA, Rodriguez B, Sieg SF, Lederman MM. Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome. Blood. 2012;120(23):4599-608. PubMed PMID: PMC3512236. doi: 10.1182/blood-2012-05-433946
26. Pallikkuth S, Pahwa R, Kausalya B, Saravanan S, Pan L, Vignesh R, Iqbal S, Solomon SS, Murugavel KG, Poongulali S, Kumarasamy N, Pahwa S. Cardiac morbidity in HIV infection is associated with checkpoint inhibitor LAG-3 on CD4 T cells. PLoS One. 2018;13(10):e0206256. PubMed PMID: PMC6209232. doi: 10.1371/journal.pone.0206256
27. 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;121(15):2914-22. PubMed PMID: PMC3624937. doi: 10.1182/blood-2012-07-445783
28. Zeng M, Southern PJ, Reilly CS, Beilman GJ, Chipman JG, Schacker TW, Haase AT. Lymphoid tissue damage in HIV-1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog. 2012;8(1):e1002437. PubMed PMID: PMC3252371. doi: 10.1371/journal.ppat.1002437
29. Shive CL, Mudd JC, Funderburg NT, Sieg SF, Kyi B, Bazdar DA, Mangioni D, Gori A, Jacobson JM, Brooks AD, Hardacre J, Ammori J, Estes JD, Schacker TW, Rodriguez B, Lederman MM. Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease. J Infect Dis. 2014;210(4):619-29. PubMed PMID: PMC4172041. doi: 10.1093/infdis/jiu125
30. Sherman KE, Abdel-Hameed E, Rouster SD, Shata MTM, Blackard JT, Safaie P, Kroner B, Preiss L, Horn PS, Kottilil S. Improvement in Hepatic Fibrosis Biomarkers Associated With Chemokine Receptor Inactivation Through Mutation or Therapeutic Blockade. Clin Infect Dis. 2019;68(11):1911-8. PubMed PMID: PMC6784280. doi: 10.1093/cid/ciy807
31. D’Antoni ML, Paul RH, Mitchell BI, Kohorn L, Fischer L, Lefebvre E, Seyedkazemi S, Nakamoto BK, Walker M, Kallianpur KJ, Ogata-Arakaki D, Ndhlovu LC, Shikuma C. Improved Cognitive Performance and Reduced Monocyte Activation in Virally Suppressed Chronic HIV After Dual CCR2 and CCR5 Antagonism. J Acquir Immune Defic Syndr. 2018;79(1):108-16. PubMed PMID: PMC6092236. doi: 10.1097/QAI.0000000000001752
32. Hunt PW, Shulman NS, Hayes TL, Dahl V, Somsouk M, Funderburg NT, McLaughlin B, Landay AL, Adeyemi O, Gilman LE, Clagett B, Rodriguez B, Martin JN, Schacker TW, Shacklett BL, Palmer S, Lederman MM, Deeks SG. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood. 2013;121(23):4635-46. PubMed PMID: PMC3685899. doi: 10.1182/blood-2012-06-436345
33. Sauce D, Larsen M, Fastenackels S, Pauchard M, Ait-Mohand H, Schneider L, Guihot A, Boufassa F, Zaunders J, Iguertsira M, Bailey M, Gorochov G, Duvivier C, Carcelain G, Kelleher AD, Simon A, Meyer L, Costagliola D, Deeks SG, Lambotte O, Autran B, Hunt PW, Katlama C, Appay V. HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood. 2011;117(19):5142-51. PubMed PMID: PMC3109539. doi: 10.1182/blood-2011-01-331306
34. McNamara RP, Costantini LM, Myers TA, Schouest B, Maness NJ, Griffith JD, Damania BA, MacLean AG, Dittmer DP. Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses. MBio. 2018;9(1). PubMed PMID: PMC5801467. doi: 10.1128/mBio.02344-17
35. Banga R, Procopio FA, Noto A, Pollakis G, Cavassini M, Ohmiti K, Corpataux JM, de Leval L, Pantaleo G, Perreau M. PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med. 2016;22(7):754-61. PubMed PMID. doi: 10.1038/nm.4113
36. McComsey GA, Daar ES, O’Riordan M, Collier AC, Kosmiski L, Santana JL, Fichtenbaum CJ, Fink H, Sax PE, Libutti DE, Gerschenson M. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202. J Infect Dis. 2013;207(4):604-11. PubMed PMID: PMC3549598. doi: 10.1093/infdis/jis720
37. 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
38. Justice AC, Erlandson KM, Hunt PW, Landay A, Miotti P, Tracy RP. Can Biomarkers Advance HIV Research and Care in the Antiretroviral Therapy Era? J Infect Dis. 2018;217(4):521-8. PubMed PMID: PMC5853399. doi: 10.1093/infdis/jix586
39. Ivanov, II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485-98. PubMed PMID: PMC2796826. doi: 10.1016/j.cell.2009.09.033
40. Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M, Franzosa EA, Horst RT, Jansen T, Jacobs L, Bonder MJ, Kurilshikov A, Fu J, Joosten LAB, Zhernakova A, Huttenhower C, Wijmenga C, Netea MG, Xavier RJ. Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell. 2016;167(7):1897. PubMed PMID. doi: 10.1016/j.cell.2016.11.046
41. Omenetti S, Pizarro TT. The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome. Front Immunol. 2015;6:639. PubMed PMID: PMC4681807. doi: 10.3389/fimmu.2015.00639
42. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365-71. PubMed PMID. doi: 10.1038/nm1511
43. 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 ML, Jabs DA, Lederman MM. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis. 2014;210(8):1228-38. PubMed PMID: PMC4192038. doi: 10.1093/infdis/jiu238
44. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280(5362):427-31. PubMed PMID. doi: 10.1126/science.280.5362.427
45. Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, Lopez P, Shet A, Low A, Mohri H, Boden D, Racz P, Markowitz M. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 2006;3(12):e484. PubMed PMID: PMC1762085. doi: 10.1371/journal.pmed.0030484
46. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16(6):341-52. PubMed PMID: PMC5541232. doi: 10.1038/nri.2016.42
47. Tang WH, Kitai T, Hazen SL. Gut Microbiota in Cardiovascular Health and Disease. Circ Res. 2017;120(7):1183-96. PubMed PMID: PMC5390330. doi: 10.1161/CIRCRESAHA.117.309715
48. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15(7):397-411. PubMed PMID: PMC6319369. doi: 10.1038/s41575-018-0011-z
49. Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The Central Nervous System and the Gut Microbiome. Cell. 2016;167(4):915-32. PubMed PMID: PMC5127403. doi: 10.1016/j.cell.2016.10.027
50. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Cancer Cell. 2018;33(4):570-80. PubMed PMID: PMC6529202. doi: 10.1016/j.ccell.2018.03.015
51. Elinav E, Garrett WS, Trinchieri G, Wargo J. The cancer microbiome. Nat Rev Cancer. 2019;19(7):371-6. PubMed PMID: PMC6700740. doi: 10.1038/s41568-019-0155-3
52. Levy M, Blacher E, Elinav E. Microbiome, metabolites and host immunity. Curr Opin Microbiol. 2017;35:8-15. PubMed PMID. doi: 10.1016/j.mib.2016.10.003
53. Postler TS, Ghosh S. Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System. Cell Metab. 2017;26(1):110-30. PubMed PMID: PMC5535818. doi: 10.1016/j.cmet.2017.05.008
54. Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, Knight R, Fontenot AP, Palmer BE. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013;14(3):329-39. PubMed PMID: PMC3864811. doi: 10.1016/j.chom.2013.08.006
55. Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, Hernandez RD, Lederman MM, Huang Y, Somsouk M, Deeks SG, Hunt PW, Lynch SV, McCune JM. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013;5(193):193ra91. PubMed PMID: PMC4094294. doi: 10.1126/scitranslmed.3006438
56. Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK, Gianella S, Siewe B, Smith DM, Landay AL, Robertson CE, Frank DN, Wilson CC. 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. PubMed PMID: PMC4062575. doi: 10.1038/mi.2013.116
57. Monaco CL, Gootenberg DB, Zhao G, Handley SA, Ghebremichael MS, Lim ES, Lankowski A, Baldridge MT, Wilen CB, Flagg M, Norman JM, Keller BC, Luevano JM, Wang D, Boum Y, Martin JN, Hunt PW, Bangsberg DR, Siedner MJ, Kwon DS, Virgin HW. Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome. Cell Host Microbe. 2016;19(3):311-22. PubMed PMID: PMC4821831. doi: 10.1016/j.chom.2016.02.011
58. Noguera-Julian M, Rocafort M, Guillen Y, Rivera J, Casadella M, Nowak P, Hildebrand F, Zeller G, Parera M, Bellido R, Rodriguez C, Carrillo J, Mothe B, Coll J, Bravo I, Estany C, Herrero C, Saz J, Sirera G, Torrela A, Navarro J, Crespo M, Brander C, Negredo E, Blanco J, Guarner F, Calle ML, Bork P, Sonnerborg A, Clotet B, Paredes R. Gut Microbiota Linked to Sexual Preference and HIV Infection. EBioMedicine. 2016;5:135-46. PubMed PMID: PMC4816837. doi: 10.1016/j.ebiom.2016.01.032
59. Rocafort M, Noguera-Julian M, Rivera J, Pastor L, Guillen Y, Langhorst J, Parera M, Mandomando I, Carrillo J, Urrea V, Rodriguez C, Casadella M, Calle ML, Clotet B, Blanco J, Naniche D, Paredes R. Evolution of the gut microbiome following acute HIV-1 infection. Microbiome. 2019;7(1):73. PubMed PMID: PMC6511141. doi: 10.1186/s40168-019-0687-5
60. Armstrong AJS, Shaffer M, Nusbacher NM, Griesmer C, Fiorillo S, Schneider JM, Preston Neff C, Li SX, Fontenot AP, Campbell T, Palmer BE, Lozupone CA. An exploration of Prevotella-rich microbiomes in HIV and men who have sex with men. Microbiome. 2018;6(1):198. PubMed PMID: PMC6219090. doi: 10.1186/s40168-018-0580-7
61. Vujkovic-Cvijin I, Somsouk M. HIV and the Gut Microbiota: Composition, Consequences, and Avenues for Amelioration. Curr HIV/AIDS Rep. 2019;16(3):204-13. PubMed PMID: PMC6579656. doi: 10.1007/s11904-019-00441-w
62. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105-8. PubMed PMID: PMC3368382. doi: 10.1126/science.1208344
63. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222-7. PubMed PMID: PMC3376388. doi: 10.1038/nature11053
64. Neff CP, Krueger O, Xiong K, Arif S, Nusbacher N, Schneider JM, Cunningham AW, Armstrong A, Li S, McCarter MD, Campbell TB, Lozupone CA, Palmer BE. Fecal Microbiota Composition Drives Immune Activation in HIV-infected Individuals. EBioMedicine. 2018;30:192-202. PubMed PMID: PMC5952409. doi: 10.1016/j.ebiom.2018.03.024
65. Nowak P, Troseid M, Avershina E, Barqasho B, Neogi U, Holm K, Hov JR, Noyan K, Vesterbacka J, Svard J, Rudi K, Sonnerborg A. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS. 2015;29(18):2409-18. PubMed PMID. doi: 10.1097/QAD.0000000000000869
66. Kaur US, Shet A, Rajnala N, Gopalan BP, Moar P, D H, Singh BP, Chaturvedi R, Tandon R. High Abundance of genus Prevotella in the gut of perinatally HIV-infected children is associated with IP-10 levels despite therapy. Sci Rep. 2018;8(1):17679. PubMed PMID: PMC6281660. doi: 10.1038/s41598-018-35877-4
67. Prasitsuebsai W, Sethaputra C, Lumbiganon P, Hansudewechakul R, Chokephaibulkit K, Truong KH, Nguyen LV, Mohd Razali KA, Nik Yusoff NK, Fong MS, Teeraananchai S, Ananworanich J, Durier N, Asia-Pacific TAAsgoI. Adherence to antiretroviral therapy, stigma and behavioral risk factors in HIV-infected adolescents in Asia. AIDS Care. 2018;30(6):727-33. PubMed PMID: PMC5912939. doi: 10.1080/09540121.2018.1425363
68. Vazquez-Castellanos JF, Serrano-Villar S, Latorre A, Artacho A, Ferrus ML, Madrid N, Vallejo A, Sainz T, Martinez-Botas J, Ferrando-Martinez S, Vera M, Dronda F, Leal M, Del Romero J, Moreno S, Estrada V, Gosalbes MJ, Moya A. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals. Mucosal Immunol. 2015;8(4):760-72. PubMed PMID. doi: 10.1038/mi.2014.107
69. Hoel H, Hove-Skovsgaard M, Hov JR, Gaardbo JC, Holm K, Kummen M, Rudi K, Nwosu F, Valeur J, Gelpi M, Seljeflot I, Ueland PM, Gerstoft J, Ullum H, Aukrust P, Nielsen SD, Troseid M. Impact of HIV and Type 2 diabetes on Gut Microbiota Diversity, Tryptophan Catabolism and Endothelial Dysfunction. Sci Rep. 2018;8(1):6725. PubMed PMID: PMC5928109. doi: 10.1038/s41598-018-25168-3
70. Vesterbacka J, Rivera J, Noyan K, Parera M, Neogi U, Calle M, Paredes R, Sonnerborg A, Noguera-Julian M, Nowak P. Richer gut microbiota with distinct metabolic profile in HIV infected Elite Controllers. Sci Rep. 2017;7(1):6269. PubMed PMID: PMC5524949. doi: 10.1038/s41598-017-06675-1
71. Handley SA, Thackray LB, Zhao G, Presti R, Miller AD, Droit L, Abbink P, Maxfield LF, Kambal A, Duan E, Stanley K, Kramer J, Macri SC, Permar SR, Schmitz JE, Mansfield K, Brenchley JM, Veazey RS, Stappenbeck TS, Wang D, Barouch DH, Virgin HW. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell. 2012;151(2):253-66. PubMed PMID: PMC3490196. doi: 10.1016/j.cell.2012.09.024
72. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63. PubMed PMID: PMC3086762. doi: 10.1038/nature09922
73. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575-84. PubMed PMID: PMC3701945. doi: 10.1056/NEJMoa1109400
74. Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, Wu X, DeStefano Shields CE, Hechenbleikner EM, Huso DL, Anders RA, Giardiello FM, Wick EC, Wang H, Wu S, Pardoll DM, Housseau F, Sears CL. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science. 2018;359(6375):592-7. PubMed PMID: PMC5881113. doi: 10.1126/science.aah3648
75. Dejea CM, Wick EC, Hechenbleikner EM, White JR, Mark Welch JL, Rossetti BJ, Peterson SN, Snesrud EC, Borisy GG, Lazarev M, Stein E, Vadivelu J, Roslani AC, Malik AA, Wanyiri JW, Goh KL, Thevambiga I, Fu K, Wan F, Llosa N, Housseau F, Romans K, Wu X, McAllister FM, Wu S, Vogelstein B, Kinzler KW, Pardoll DM, Sears CL. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A. 2014;111(51):18321-6. PubMed PMID: PMC4280621. doi: 10.1073/pnas.1406199111
76. Budden KF, Shukla SD, Rehman SF, Bowerman KL, Keely S, Hugenholtz P, Armstrong-James DPH, Adcock IM, Chotirmall SH, Chung KF, Hansbro PM. Functional effects of the microbiota in chronic respiratory disease. Lancet Respir Med. 2019;7(10):907-20. PubMed PMID. doi: 10.1016/S2213-2600(18)30510-1
77. Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, Doyle J, Jewell L, De Simone C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology. 2001;121(3):580-91. PubMed PMID. doi: 10.1053/gast.2001.27224
78. Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson A, Weir TL, Ehrentraut SF, Pickel C, Kuhn KA, Lanis JM, Nguyen V, Taylor CT, Colgan SP. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe. 2015;17(5):662-71. PubMed PMID: PMC4433427. doi: 10.1016/j.chom.2015.03.005
79. Franzosa EA, Sirota-Madi A, Avila-Pacheco J, Fornelos N, Haiser HJ, Reinker S, Vatanen T, Hall AB, Mallick H, McIver LJ, Sauk JS, Wilson RG, Stevens BW, Scott JM, Pierce K, Deik AA, Bullock K, Imhann F, Porter JA, Zhernakova A, Fu J, Weersma RK, Wijmenga C, Clish CB, Vlamakis H, Huttenhower C, Xavier RJ. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol. 2019;4(2):293-305. PubMed PMID: PMC6342642. doi: 10.1038/s41564-018-0306-4
80. Weingarden AR, Vaughn BP. Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease. Gut Microbes. 2017;8(3):238-52. PubMed PMID: PMC5479396. doi: 10.1080/19490976.2017.1290757
81. Kardashian A, Ma Y, Yin MT, Scherzer R, Nolan O, Aweeka F, Tien PC, Price JC. High Kynurenine:Tryptophan Ratio Is Associated With Liver Fibrosis in HIV-Monoinfected and HIV/Hepatitis C Virus-Coinfected Women. Open Forum Infect Dis. 2019;6(7):ofz281. PubMed PMID: PMC6612851. doi: 10.1093/ofid/ofz281
82. Sinha A, Ma Y, Scherzer R, Rahalkar S, Neilan BD, Crane H, Drozd D, Martin J, Deeks SG, Hunt P, Hsue PY. Carnitine Is Associated With Atherosclerotic Risk and Myocardial Infarction in HIV -Infected Adults. J Am Heart Assoc. 2019;8(9):e011037. PubMed PMID: PMC6512101. doi: 10.1161/JAHA.118.011037
83. Kehrmann J, Menzel J, Saeedghalati M, Obeid R, Schulze C, Holzendorf V, Farahpour F, Reinsch N, Klein-Hitpass L, Streeck H, Hoffmann D, Buer J, Esser S, Group H-HS. Gut Microbiota in Human Immunodeficiency Virus-Infected Individuals Linked to Coronary Heart Disease. J Infect Dis. 2019;219(3):497-508. PubMed PMID. doi: 10.1093/infdis/jiy524
84. Missailidis C, Neogi U, Stenvinkel P, Troseid M, Nowak P, Bergman P. The microbial metabolite trimethylamine-N-oxide in association with inflammation and microbial dysregulation in three HIV cohorts at various disease stages. AIDS. 2018;32(12):1589-98. PubMed PMID. doi: 10.1097/QAD.0000000000001813
85. Keegan MR, Chittiprol S, Letendre SL, Winston A, Fuchs D, Boasso A, Iudicello J, Ellis RJ. Tryptophan Metabolism and Its Relationship with Depression and Cognitive Impairment Among HIV-infected Individuals. Int J Tryptophan Res. 2016;9:79-88. PubMed PMID: PMC5083113. doi: 10.4137/IJTR.S36464
86. Cassol E, Misra V, Morgello S, Kirk GD, Mehta SH, Gabuzda D. Altered Monoamine and Acylcarnitine Metabolites in HIV-Positive and HIV-Negative Subjects With Depression. J Acquir Immune Defic Syndr. 2015;69(1):18-28. PubMed PMID: PMC4562456. doi: 10.1097/QAI.0000000000000551
87. Martinez P, Tsai AC, Muzoora C, Kembabazi A, Weiser SD, Huang Y, Haberer JE, Martin JN, Bangsberg DR, Hunt PW. Reversal of the Kynurenine pathway of tryptophan catabolism may improve depression in ART-treated HIV-infected Ugandans. J Acquir Immune Defic Syndr. 2014;65(4):456-62. PubMed PMID: PMC3943704. doi: 10.1097/QAI.0000000000000062
88. Pinto-Cardoso S, Klatt NR, Reyes-Teran G. Impact of antiretroviral drugs on the microbiome: unknown answers to important questions. Curr Opin HIV AIDS. 2018;13(1):53-60. PubMed PMID: PMC5718259. doi: 10.1097/COH.0000000000000428
89. Villanueva-Millan MJ, Perez-Matute P, Recio-Fernandez E, Lezana Rosales JM, Oteo JA. Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV-infected patients. J Int AIDS Soc. 2017;20(1):21526. PubMed PMID: PMC5467634. doi: 10.7448/IAS.20.1.21526
90. Pinto-Cardoso S, Lozupone C, Briceno O, Alva-Hernandez S, Tellez N, Adriana A, Murakami-Ogasawara A, Reyes-Teran G. Fecal Bacterial Communities in treated HIV infected individuals on two antiretroviral regimens. Sci Rep. 2017;7:43741. PubMed PMID: PMC5338340. doi: 10.1038/srep43741
91. Abdool Karim SS, Baxter C, Passmore JS, McKinnon LR, Williams BL. The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women. J Int AIDS Soc. 2019;22(5):e25300. PubMed PMID: PMC6541743. doi: 10.1002/jia2.25300
92. Anderson D, Politch JA, Pudney J. HIV infection and immune defense of the penis. Am J Reprod Immunol. 2011;65(3):220-9. PubMed PMID: PMC3076079. doi: 10.1111/j.1600-0897.2010.00941.x
93. Williams WB, Han Q, Haynes BF. Cross-reactivity of HIV vaccine responses and the microbiome. Curr Opin HIV AIDS. 2018;13(1):9-14. PubMed PMID: PMC5890927. doi: 10.1097/COH.0000000000000423
94. Williams WB, Liao HX, Moody MA, Kepler TB, Alam SM, Gao F, Wiehe K, Trama AM, Jones K, Zhang R, Song H, Marshall DJ, Whitesides JF, Sawatzki K, Hua A, Liu P, Tay MZ, Seaton KE, Shen X, Foulger A, Lloyd KE, Parks R, Pollara J, Ferrari G, Yu JS, Vandergrift N, Montefiori DC, Sobieszczyk ME, Hammer S, Karuna S, Gilbert P, Grove D, Grunenberg N, McElrath MJ, Mascola JR, Koup RA, Corey L, Nabel GJ, Morgan C, Churchyard G, Maenza J, Keefer M, Graham BS, Baden LR, Tomaras GD, Haynes BF. HIV-1 VACCINES. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies. Science. 2015;349(6249):aab1253. PubMed PMID: PMC4562404. doi: 10.1126/science.aab1253
95. Klatt NR, Cheu R, Birse K, Zevin AS, Perner M, Noel-Romas L, Grobler A, Westmacott G, Xie IY, Butler J, Mansoor L, McKinnon LR, Passmore JS, Abdool Karim Q, Abdool Karim SS, Burgener AD. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356(6341):938-45. PubMed PMID. doi: 10.1126/science.aai9383
96. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97-103. PubMed PMID: PMC5827966. doi: 10.1126/science.aan4236
97. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-84. PubMed PMID: PMC4721659. doi: 10.1126/science.aad1329
98. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084-9. PubMed PMID: PMC4873287. doi: 10.1126/science.aac4255
99. Overton ET, Yeh E, Presti R, Jacobson J, Williams B, Wilson C, Landay A, Brenchley J, Dube M, Fichtenbaum CJ, Utay NS, Kitch DW, Andrade A. Assessing the Probiotic Effect in Treated HIV: Results of ACTG A5350. CROI; Seattle, WA2019.
100. Wada N, Jacobson LP, Cohen M, French A, Phair J, Munoz A. Cause-specific life expectancies after 35 years of age for human immunodeficiency syndrome-infected and human immunodeficiency syndrome-negative individuals followed simultaneously in long-term cohort studies, 1984-2008. Am J Epidemiol. 2013;177(2):116-25. PubMed PMID: PMC3590031. doi: 10.1093/aje/kws321
101. High KP, Brennan-Ing M, Clifford DB, Cohen MH, Currier J, Deeks SG, Deren S, Effros RB, Gebo K, Goronzy JJ, Justice AC, Landay A, Levin J, Miotti PG, Munk RJ, Nass H, Rinaldo CR, Jr., Shlipak MG, Tracy R, Valcour V, Vance DE, Walston JD, Volberding P, HIV OARWGo, Aging. 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 Suppl 1:S1-18. PubMed PMID: PMC3413877. doi: 10.1097/QAI.0b013e31825a3668
102. Cole JH, Underwood J, Caan MW, De Francesco D, van Zoest RA, Leech R, Wit FW, Portegies P, Geurtsen GJ, Schmand BA, Schim van der Loeff MF, Franceschi C, Sabin CA, Majoie CB, Winston A, Reiss P, Sharp DJ, collaboration C. Increased brain-predicted aging in treated HIV disease. Neurology. 2017;88(14):1349-57. PubMed PMID: PMC5379929. doi: 10.1212/WNL.0000000000003790
103. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, Berti A, Rossi E, Roverato A, Palella F. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53(11):1120-6. PubMed PMID. doi: 10.1093/cid/cir627
104. Schrack JA, Althoff KN, Jacobson LP, Erlandson KM, Jamieson BD, Koletar SL, Phair J, Ferrucci L, Brown TT, Margolick JB, Multicenter ACS. Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men. J Acquir Immune Defic Syndr. 2015;70(4):370-6. PubMed PMID: PMC4624470. doi: 10.1097/QAI.0000000000000731
105. Schrack JA, Jacobson LP, Althoff KN, Erlandson KM, Jamieson BD, Koletar SL, Phair J, Brown TT, Margolick JB, Multicenter ACS. Effect of HIV-infection and cumulative viral load on age-related decline in grip strength. AIDS. 2016;30(17):2645-52. PubMed PMID: PMC5083134. doi: 10.1097/QAD.0000000000001245
106. Althoff KN, Jacobson LP, Cranston RD, Detels R, Phair JP, Li X, Margolick JB, Multicenter ACS. Age, comorbidities, and AIDS predict a frailty phenotype in men who have sex with men. J Gerontol A Biol Sci Med Sci. 2014;69(2):189-98. PubMed PMID: PMC4038242. doi: 10.1093/gerona/glt148
107. Guaraldi G, De Francesco D, Milic J, Franconi I, Mussini C, Falutz J, Cesari M. The Interplay Between Age and Frailty in People Living With HIV: Results From an 11-Year Follow-up Observational Study. Open Forum Infect Dis. 2019;6(5):ofz199. PubMed PMID: PMC6524826. doi: 10.1093/ofid/ofz199
108. Lagathu C, Cossarizza A, Bereziat V, Nasi M, Capeau J, Pinti M. Basic science and pathogenesis of ageing with HIV: potential mechanisms and biomarkers. AIDS. 2017;31 Suppl 2:S105-S19. PubMed PMID. doi: 10.1097/QAD.0000000000001441
109. Rasmussen LD, May MT, Kronborg G, Larsen CS, Pedersen C, Gerstoft J, Obel N. Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study. Lancet HIV. 2015;2(7):e288-98. PubMed PMID. doi: 10.1016/S2352-3018(15)00077-6
110. 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, Group ISS. 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
111. Margolick JB, Bream JH, Nilles TL, Li H, Langan SJ, Deng S, Wang R, Wada N, Leng SX. Relationship Between T-Cell Responses to CMV, Markers of Inflammation, and Frailty in HIV-uninfected and HIV-infected Men in the Multicenter AIDS Cohort Study. J Infect Dis. 2018;218(2):249-58. PubMed PMID: PMC6009694. doi: 10.1093/infdis/jiy005
112. Lee SA, Sinclair E, Jain V, Huang Y, Epling L, Van Natta M, Meinert CL, Martin JN, McCune JM, Deeks SG, Lederman MM, Hecht FM, Hunt PW. Low proportions of CD28- CD8+ T cells expressing CD57 can be reversed by early ART initiation and predict mortality in treated HIV infection. J Infect Dis. 2014;210(3):374-82. PubMed PMID: PMC4110459. doi: 10.1093/infdis/jiu109
113. Lee SA, Sinclair E, Hatano H, Hsue PY, Epling L, Hecht FM, Bangsberg DR, Martin JN, McCune JM, Deeks SG, Hunt PW. Impact of HIV on CD8+ T cell CD57 expression is distinct from that of CMV and aging. PLoS One. 2014;9(2):e89444. PubMed PMID: PMC3937334. doi: 10.1371/journal.pone.0089444
114. Whetten K, Reif S, Whetten R, Murphy-McMillan LK. Trauma, mental health, distrust, and stigma among HIV-positive persons: implications for effective care. Psychosom Med. 2008;70(5):531-8. PubMed PMID. doi: 10.1097/PSY.0b013e31817749dc
115. George VK, Pallikkuth S, Parmigiani A, Alcaide M, Fischl M, Arheart KL, Pahwa S. HIV infection Worsens Age-Associated Defects in Antibody Responses to Influenza Vaccine. J Infect Dis. 2015;211(12):1959-68. PubMed PMID: PMC4836723. doi: 10.1093/infdis/jiu840
116. de Armas LR, Pallikkuth S, George V, Rinaldi S, Pahwa R, Arheart KL, Pahwa S. Reevaluation of immune activation in the era of cART and an aging HIV-infected population. JCI Insight. 2017;2(20). PubMed PMID: PMC5846952. doi: 10.1172/jci.insight.95726
117. Pallikkuth S, De Armas LR, Pahwa R, Rinaldi S, George VK, Sanchez CM, Pan L, Dickinson G, Rodriguez A, Fischl M, Alcaide M, Pahwa S. Impact of aging and HIV infection on serologic response to seasonal influenza vaccination. AIDS. 2018;32(9):1085-94. PubMed PMID: PMC6574117. doi: 10.1097/QAD.0000000000001774
118. Pallikkuth S, de Armas LR, Rinaldi S, George VK, Pan L, Arheart KL, Pahwa R, Pahwa S. Dysfunctional peripheral T follicular helper cells dominate in people with impaired influenza vaccine responses: Results from the FLORAH study. PLoS Biol. 2019;17(5):e3000257. PubMed PMID: PMC6542545. doi: 10.1371/journal.pbio.3000257
119. Furler RL, Newcombe KL, Del Rio Estrada PM, Reyes-Teran G, Uittenbogaart CH, Nixon DF. Histoarchitectural Deterioration of Lymphoid Tissues in HIV-1 Infection and in Aging. AIDS Res Hum Retroviruses. 2019;35(11-12):1148-59. PubMed PMID: PMC6862967. doi: 10.1089/AID.2019.0156
120. Tavenier J, Margolick JB, Leng SX. T-cell immunity against cytomegalovirus in HIV infection and aging: relationships with inflammation, immune activation, and frailty. Med Microbiol Immunol. 2019;208(3-4):289-94. PubMed PMID: PMC6635075. doi: 10.1007/s00430-019-00591-z
121. Cooper CL, Galanakis C, Donelle J, Kwong J, Boyd R, Boucher L, Kendall CE. HCV-infected individuals have higher prevalence of comorbidity and multimorbidity: a retrospective cohort study. BMC Infect Dis. 2019;19(1):712. PubMed PMID: PMC6706878. doi: 10.1186/s12879-019-4315-6
122. Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, Hou L, Baccarelli AA, Li Y, Stewart JD, Whitsel EA, Assimes TL, Ferrucci L, Horvath S. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-27. PubMed PMID: PMC6366976. doi: 10.18632/aging.101684
123. Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M, Morsey BM, Swindells S, Shen H, Ng CT, Flagg K, Chen D, Zhang K, Fox HS, Ideker T. Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Mol Cell. 2016;62(2):157-68. PubMed PMID: PMC4995115. doi: 10.1016/j.molcel.2016.03.019
124. Theurey P, Pizzo P. The Aging Mitochondria. Genes (Basel). 2018;9(1). PubMed PMID: PMC5793175. doi: 10.3390/genes9010022
125. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-9. PubMed PMID. doi: 10.1093/gerona/glu057
126. van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439-46. PubMed PMID: PMC4214092. doi: 10.1038/nature13193
127. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6(12):2853-68. PubMed PMID: PMC2592359. doi: 10.1371/journal.pbio.0060301
128. Prata L, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin Immunol. 2019:101275. PubMed PMID. doi: 10.1016/j.smim.2019.04.003
129. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. PubMed PMID: PMC4166495. doi: 10.1146/annurev-pathol-121808-102144
130. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014;17(4):324-8. PubMed PMID. doi: 10.1097/MCO.0000000000000065
131. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, Wyss-Coray T, Sierra F. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709-13. PubMed PMID: PMC4852871. doi: 10.1016/j.cell.2014.10.039
132. Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV. Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS. 1996;10(8):F17-22. PubMed PMID. doi: 10.1097/00002030-199607000-00001
133. Babu H, Ambikan AT, Gabriel EE, Svensson Akusjarvi S, Palaniappan AN, Sundaraj V, Mupanni NR, Sperk M, Cheedarla N, Sridhar R, Tripathy SP, Nowak P, Hanna LE, Neogi U. Systemic Inflammation and the Increased Risk of Inflamm-Aging and Age-Associated Diseases in People Living With HIV on Long Term Suppressive Antiretroviral Therapy. Front Immunol. 2019;10:1965. PubMed PMID: PMC6718454. doi: 10.3389/fimmu.2019.01965
134. Rickabaugh TM, Kilpatrick RD, Hultin LE, Hultin PM, Hausner MA, Sugar CA, Althoff KN, Margolick JB, Rinaldo CR, Detels R, Phair J, Effros RB, Jamieson BD. The dual impact of HIV-1 infection and aging on naive CD4 T-cells: additive and distinct patterns of impairment. PLoS One. 2011;6(1):e16459. PubMed PMID: PMC3027697. doi: 10.1371/journal.pone.0016459
135. Killian MS, Monteiro J, Matud J, Hultin LE, Hausner MA, Yang OO, Gregersen PK, Detels R, Giorgi JV, Jamieson BD. Persistent alterations in the T-cell repertoires of HIV-1-infected and at-risk uninfected men. AIDS. 2004;18(2):161-70. PubMed PMID. doi: 10.1097/00002030-200401230-00004
136. Pathai S, Lawn SD, Gilbert CE, McGuinness D, McGlynn L, Weiss HA, Port J, Christ T, Barclay K, Wood R, Bekker LG, Shiels PG. Accelerated biological ageing in HIV-infected individuals in South Africa: a case-control study. AIDS. 2013;27(15):2375-84. PubMed PMID: PMC3805356. doi: 10.1097/QAD.0b013e328363bf7f
137. Kaner JD, Thibaud S, Jasra S, Wang Y, Janakiram M, Sharma A, Sridharan A, Elias H, Polineni R, Assal A, Weiss L, Braunschweig I, Steidl U, Pradhan K, Shastri A, Chaitowitz M, Zingman B, Will B, Mantzaris I, Verma A. HIV portends a poor prognosis in myelodysplastic syndromes. Leuk Lymphoma. 2019:1-7. PubMed PMID. doi: 10.1080/10428194.2019.1633631
138. Dhurve SA, Dhurve AS. Bone Marrow Abnormalities in HIV Disease. Mediterr J Hematol Infect Dis. 2013;5(1):e2013033. PubMed PMID: PMC3684351. doi: 10.4084/MJHID.2013.033
139. Szaniawski MA, Spivak AM. Senotherapeutics for HIV and aging. Curr Opin HIV AIDS. 2019. PubMed PMID. doi: 10.1097/COH.0000000000000609
140. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-6. PubMed PMID: PMC3468323. doi: 10.1038/nature10600
141. Niedernhofer LJ, Robbins PD. Senotherapeutics for healthy ageing. Nat Rev Drug Discov. 2018;17(5):377. PubMed PMID. doi: 10.1038/nrd.2018.44
142. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-63. PubMed PMID: PMC6412088. doi: 10.1016/j.ebiom.2018.12.052
143. Routy JP, Isnard S, Mehraj V, Ostrowski M, Chomont N, Ancuta P, Ponte R, Planas D, Dupuy FP, Angel JB, Lilac Study G. Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol. BMJ Open. 2019;9(4):e028444. PubMed PMID: PMC6500211. doi: 10.1136/bmjopen-2018-028444
144. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468-77. PubMed PMID: PMC4032600. doi: 10.1111/acel.12194
145. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179. PubMed PMID. doi: 10.1126/scitranslmed.3009892
146. Pandrea I, Landay A, Wilson C, Stock J, Tracy R, Apetrei C. Using the pathogenic and nonpathogenic nonhuman primate model for studying non-AIDS comorbidities. Curr HIV/AIDS Rep. 2015;12(1):54-67. PubMed PMID: PMC4369284. doi: 10.1007/s11904-014-0245-5
147. Mattison JA, Vaughan KL. An overview of nonhuman primates in aging research. Exp Gerontol. 2017;94:41-5. PubMed PMID: PMC5466843. doi: 10.1016/j.exger.2016.12.005
148. Zheng HY, Zhang MX, Chen M, Jiang J, Song JH, Lian XD, Tian RR, Zhang XL, Zhang LT, Pang W, Zhang GH, Zheng YT. Accelerated disease progression and robust innate host response in aged SIVmac239-infected Chinese rhesus macaques is associated with enhanced immunosenescence. Sci Rep. 2017;7(1):37. PubMed PMID: PMC5428349. doi: 10.1038/s41598-017-00084-0
149. Bissel SJ, Gurnsey K, Jedema HP, Smith NF, Wang G, Bradberry CW, Wiley CA. Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment. Retrovirology. 2018;15(1):17. PubMed PMID: PMC5796498. doi: 10.1186/s12977-018-0400-y