Three-Month cART Initiated During Primary HIV Does Not Correct the Structural, Immune, and Microbial Abnormalities within the Gastrointestinal Tract
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Abstract
Background: HIV infection leads to profound alterations of gut structure, immunity, and microbiome, resulting in immune activation and inflammation, which drive the development of non-infectious comorbidities. The introduction of combination antiretroviral therapy (cART) in the chronic stages of disease does not correct such abnormalities; however, the effect of viro-suppressive treatment in the gastrointestinal tract during primary HIV infection (PHI) is largely unknown. We studied the effects of 12-week cART on gastrointestinal (GI) structure, immunity, and mucosal microbiome in people living with HIV (PLWH) with PHI.
Methods: Eleven participants with PHI enrolled in the INACTION trial underwent colonoscopy with ileum and colon biopsies, as well as peripheral blood mononuclear cell (PBMC) and plasma collection, prior to and at 12 weeks of cART. Gut biopsies were stained with CD14, CD68, CD163, and E-cadherin antibodies and Masson trichrome. Flow cytometry was performed on lamina propria and PBMCs to characterize CD4, γδ T, Treg, and Th17 cells. Gut tissue-associated microbiome analysis was conducted on colon and ileum biopsies. Ten untreated individuals with chronic HIV infection (CHI) were also studied for comparative analysis.
Results: Despite treatment of PHI, gut barrier damage (E-cadherin loss, collagen deposition) progressed, with a partially preserved distribution of intestinal macrophages. Treated PHI showed stable CD4+ and γδ T-cell frequencies and decreased activation of these subsets in the colon, with no effect on intestinal Th17 and Treg cells. No major changes in peripheral inflammation and intestinal barrier integrity markers were observed. Gut tissue-associated microbiome composition evolved during cART treatment in PHI.
Conclusion: Despite early initiation, 12-week cART is unable to correct the HIV-mediated gut damage. Since gut injury drives systemic inflammation, which in turn fosters the pathogenesis of non-communicable comorbidities, our findings provide pathogenetic evidence of limited efficacy of early cART in reverting the HIV-associated pro-inflammatory signature and clinical risk.
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References
1. Group ISS, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fatkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807. doi: 10.1056/NEJMoa1506816. PubMed PMID: 26192873; PMCID: PMC4569751.
2. Marcus JL, Leyden WA, Alexeeff SE, Anderson AN, Hechter RC, Hu H, Lam JO, Towner WJ, Yuan Q, Horberg MA, Silverberg MJ. Comparison of Overall and Comorbidity-Free Life Expectancy Between Insured Adults With and Without HIV Infection, 2000-2016. JAMA Netw Open. 2020;3(6):e207954. doi: 10.1001/jamanetworkopen.2020.7954. PubMed PMID: 32539152; PMCID: PMC7296391.
3. European Centre for Disease Prevention and Control/WHO Regional Office for Europe. HIV/AIDS surveillance in Europe 2023 – 2022 data. Stockholm: ECDC; 2023.
4. Mudd JC, Brenchley JM. Gut Mucosal Barrier Dysfunction, Microbial Dysbiosis, and Their Role in HIV-1 Disease Progression. J Infect Dis. 2016;214 Suppl 2(Suppl 2):S58-66. doi: 10.1093/infdis/jiw258. PubMed PMID: 27625432; PMCID: PMC5021240.
5. Tincati C, Douek DC, Marchetti G. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection. AIDS Res Ther. 2016;13:19. doi: 10.1186/s12981-016-0103-1. PubMed PMID: 27073405; PMCID: PMC4828806.
6. Bono V, Augello M, Tincati C, Marchetti G. Failure of CD4+ T-cell Recovery upon Virally-Effective cART: an Enduring Gap in the Understanding of HIV+ Immunological non-Responders. New Microbiol. 2022;45(3):155-72. PubMed PMID: 35920870.
7. 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. doi: 10.1093/infdis/jiu238. PubMed PMID: 24755434; PMCID: PMC4192038.
8. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, Plants J, Seth A, Wilson CC, Deeks SG, Lederman MM, Landay AL. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014;210(8):1248-59. doi: 10.1093/infdis/jiu254. PubMed PMID: 24795473; PMCID: PMC4192039.
9. Grund B, Baker JV, Deeks SG, Wolfson J, Wentworth D, Cozzi-Lepri A, Cohen CJ, Phillips A, Lundgren JD, Neaton JD, Group ISESS. Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy. PLoS One. 2016;11(5):e0155100. doi: 10.1371/journal.pone.0155100. PubMed PMID: 27171281; PMCID: PMC4865234.
10. Vujkovic-Cvijin I, Sortino O, Verheij E, Sklar J, Wit FW, Kootstra NA, Sellers B, Brenchley JM, Ananworanich J, Loeff MSV, Belkaid Y, Reiss P, Sereti I. HIV-associated gut dysbiosis is independent of sexual practice and correlates with noncommunicable diseases. Nat Commun. 2020;11(1):2448. doi: 10.1038/s41467-020-16222-8. PubMed PMID: 32415070; PMCID: PMC7228978.
11. Ancona G ME, Tincati C, Barassi A, Calcagno A, Augello M, Bono V, Bai F, Cannizzo ES, d’Arminio Monforte A, Marchetti G. Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes. Frontiers in immunology2021.
12. Rhoades N, Mendoza N, Jankeel A, Sureshchandra S, Alvarez AD, Doratt B, Heidari O, Hagan R, Brown B, Scheibel S, Marbley T, Taylor J, Messaoudi I. Altered Immunity and Microbial Dysbiosis in Aged Individuals With Long-Term Controlled HIV Infection. Front Immunol. 2019;10:463. doi: 10.3389/fimmu.2019.00463. PubMed PMID: 30915086; PMCID: PMC6423162.
13. Nganou-Makamdop K, Talla A, Sharma AA, Darko S, Ransier A, Laboune F, Chipman JG, Beilman GJ, Hoskuldsson T, Fourati S, Schmidt TE, Arumugam S, Lima NS, Moon D, Callisto S, Schoephoerster J, Tomalka J, Mugyenyi P, Ssali F, Muloma P, Ssengendo P, Leda AR, Cheu RK, Flynn JK, Morou A, Brunet-Ratnasingham E, Rodriguez B, Lederman MM, Kaufmann DE, Klatt NR, Kityo C, Brenchley JM, Schacker TW, Sekaly RP, Douek DC. Translocated microbiome composition determines immunological outcome in treated HIV infection. Cell. 2021;184(15):3899-914 e16. doi: 10.1016/j.cell.2021.05.023. PubMed PMID: 34237254; PMCID: PMC8316372.
14. Serrano-Villar S, Sanchez-Carrillo S, Talavera-Rodriguez A, Lelouvier B, Gutierrez C, Vallejo A, Servant F, Bernadino JI, Estrada V, Madrid N, Gosalbes MJ, Bisbal O, de Lagarde M, Martinez-Sanz J, Ron R, Herrera S, Moreno S, Ferrer M. Blood Bacterial Profiles Associated With Human Immunodeficiency Virus Infection and Immune Recovery. J Infect Dis. 2021;223(3):471-81. doi: 10.1093/infdis/jiaa379. PubMed PMID: 32601702.
15. Ferrari B, Da Silva AC, Liu KH, Saidakova EV, Korolevskaya LB, Shmagel KV, Shive C, Pacheco Sanchez G, Retuerto M, Sharma AA, Ghneim K, Noel-Romas L, Rodriguez B, Ghannoum MA, Hunt PP, Deeks SG, Burgener AD, Jones DP, Dobre MA, Marconi VC, Sekaly RP, Younes SA. Gut-derived bacterial toxins impair memory CD4+ T-cell mitochondrial function in HIV-1 infection. J Clin Invest. 2022;132(9). doi: 10.1172/JCI149571. PubMed PMID: 35316209; PMCID: PMC9057623.
16. Nystrom S, Govender M, Yap SH, Kamarulzaman A, Rajasuriar R, Larsson M. HIV-Infected Individuals on ART With Impaired Immune Recovery Have Altered Plasma Metabolite Profiles. Open Forum Infect Dis. 2021;8(7):ofab288. doi: 10.1093/ofid/ofab288. PubMed PMID: 34258318; PMCID: PMC8271132.
17. Zhang W, Ruan L. Recent advances in poor HIV immune reconstitution: what will the future look like? Front Microbiol. 2023;14:1236460. doi: 10.3389/fmicb.2023.1236460. PubMed PMID: 37608956; PMCID: PMC10440441.
18. Tincati C, Merlini E, Braidotti P, Ancona G, Savi F, Tosi D, Borghi E, Callegari ML, Mangiavillano B, Barassi A, Bulfamante G, d’Arminio Monforte A, Romagnoli S, Chomont N, Marchetti G. Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy. AIDS. 2016;30(7):991-1003. doi: 10.1097/QAD.0000000000001015. PubMed PMID: 27028142.
19. Chung CY, Alden SL, Funderburg NT, Fu P, Levine AD. Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog. 2014;10(6):e1004198. doi: 10.1371/journal.ppat.1004198. PubMed PMID: 24968145; PMCID: PMC4072797.
20. Somsouk M, Estes JD, Deleage C, Dunham RM, Albright R, Inadomi JM, Martin JN, Deeks SG, McCune JM, Hunt PW. Gut epithelial barrier and systemic inflammation during chronic HIV infection. AIDS. 2015;29(1):43-51. doi: 10.1097/QAD.0000000000000511. PubMed PMID: 25387317; PMCID: PMC4444362.
21. Guillen Y, Noguera-Julian M, Rivera J, Casadella M, Zevin AS, Rocafort M, Parera M, Rodriguez C, Arumi M, Carrillo J, Mothe B, Estany C, Coll J, Bravo I, Herrero C, Saz J, Sirera G, Torrella A, Navarro J, Crespo M, Negredo E, Brander C, Blanco J, Calle ML, Klatt NR, Clotet B, Paredes R. Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection. Mucosal Immunol. 2019;12(1):232-46. doi: 10.1038/s41385-018-0083-7. PubMed PMID: 30171206.
22. Tincati C, Bono V, Cannizzo ES, Tosi D, Savi F, Falcinella C, Casabianca A, Orlandi C, Luigiano C, Augello M, Rusconi S, Muscatello A, Bandera A, Calcagno A, Gori A, Nozza S, Marchetti G, on behalf of the Italian Network of AHIVI. Primary HIV infection features colonic damage and neutrophil inflammation yet containment of microbial translocation. AIDS. 2024;38(5):623-32. doi: 10.1097/QAD.0000000000003799. PubMed PMID: 38016163; PMCID: PMC10942218.
23. Deleage C, Schuetz A, Alvord WG, Johnston L, Hao XP, Morcock DR, Rerknimitr R, Fletcher JL, Puttamaswin S, Phanuphak N, Dewar R, McCune JM, Sereti I, Robb M, Kim JH, Schacker TW, Hunt P, Lifson JD, Ananworanich J, Estes JD. Impact of early cART in the gut during acute HIV infection. JCI Insight. 2016;1(10). doi: 10.1172/jci.insight.87065. PubMed PMID: 27446990; PMCID: PMC4951101.
24. Schuetz A, Deleage C, Sereti I, Rerknimitr R, Phanuphak N, Phuang-Ngern Y, Estes JD, Sandler NG, Sukhumvittaya S, Marovich M, Jongrakthaitae S, Akapirat S, Fletscher JL, Kroon E, Dewar R, Trichavaroj R, Chomchey N, Douek DC, RJ OC, Ngauy V, Robb ML, Phanuphak P, Michael NL, Excler JL, Kim JH, de Souza MS, Ananworanich J, Rv254/Search, Groups RSS. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog. 2014;10(12):e1004543. doi: 10.1371/journal.ppat.1004543. PubMed PMID: 25503054; PMCID: PMC4263756.
25. Sereti I, Krebs SJ, Phanuphak N, Fletcher JL, Slike B, Pinyakorn S, O’Connell RJ, Rupert A, Chomont N, Valcour V, Kim JH, Robb ML, Michael NL, Douek DC, Ananworanich J, Utay NS, Rv254/Search RS, teams Sp. Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection. Clin Infect Dis. 2017;64(2):124-31. doi: 10.1093/cid/ciw683. PubMed PMID: 27737952; PMCID: PMC5215214.
26. Sortino O, Phanuphak N, Schuetz A, Ortiz AM, Chomchey N, Belkaid Y, Davis J, Mystakelis HA, Quinones M, Deleage C, Ingram B, Rerknimitr R, Pinyakorn S, Rupert A, Robb ML, Ananworanich J, Brenchley J, Sereti I, Group RSS. Impact of Acute HIV Infection and Early Antiretroviral Therapy on the Human Gut Microbiome. Open Forum Infect Dis. 2020;7(12):ofz367. doi: 10.1093/ofid/ofz367. PubMed PMID: 33324725; PMCID: PMC7724511.
27. Bruzzesi E, Gabrieli A, Bernasconi D, Marchetti G, Calcagno A, Ripamonti D, Antinori A, Squillace N, Cingolani A, Muscatello A, Bandera A, Gori A, Rusconi S, Nozza S, Group IS. HIV-DNA decrease during treatment in primary HIV-1 infection with three different drug regimens: Italian Network of Acute HIV Infection (INACTION) clinical trial. J Med Virol. 2023;95(9):e29114. doi: 10.1002/jmv.29114. PubMed PMID: 37752816.
28. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010;10(1):11-23. doi: 10.1038/nri2674. PubMed PMID: 20010788; PMCID: PMC3119211.
29. Brantly A, Yeakle K, Bouchard MJ, Gaskill PJ, Nonnemacher MR. The role of liver macrophages in viral liver pathogenesis. J Leukoc Biol. 2025;117(9). doi: 10.1093/jleuko/qiaf088. PubMed PMID: 40561105; PMCID: PMC12400039.
30. Escudie F, Auer L, Bernard M, Mariadassou M, Cauquil L, Vidal K, Maman S, Hernandez-Raquet G, Combes S, Pascal G. FROGS: Find, Rapidly, OTUs with Galaxy Solution. Bioinformatics. 2018;34(8):1287-94. doi: 10.1093/bioinformatics/btx791. PubMed PMID: 29228191.
31. Anhe FF, Jensen BAH, Varin TV, Servant F, Van Blerk S, Richard D, Marceau S, Surette M, Biertho L, Lelouvier B, Schertzer JD, Tchernof A, Marette A. Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity. Nat Metab. 2020;2(3):233-42. doi: 10.1038/s42255-020-0178-9. PubMed PMID: 32694777.
32. Klatt NR, Funderburg NT, Brenchley JM. Microbial translocation, immune activation, and HIV disease. Trends Microbiol. 2013;21(1):6-13. doi: 10.1016/j.tim.2012.09.001. PubMed PMID: 23062765; PMCID: PMC3534808.
33. Raehtz KD, Pandrea I, Apetrei C. It’s all in the gut: the central role of the gut and microbiome in preventing disease progression in simian immunodeficiency viruses infected African nonhuman primates. Curr Opin HIV AIDS. 2025;20(2):124-32. doi: 10.1097/COH.0000000000000911. PubMed PMID: 39774258; PMCID: PMC11802300.
34. Brenchley JM. Mucosal immunity in human and simian immunodeficiency lentivirus infections. Mucosal Immunol. 2013;6(4):657-65. doi: 10.1038/mi.2013.15. PubMed PMID: 23549448; PMCID: PMC4154146.
35. Le Hingrat Q, Sereti I, Landay AL, Pandrea I, Apetrei C. The Hitchhiker Guide to CD4(+) T-Cell Depletion in Lentiviral Infection. A Critical Review of the Dynamics of the CD4(+) T Cells in SIV and HIV Infection. Front Immunol. 2021;12:695674. doi: 10.3389/fimmu.2021.695674. PubMed PMID: 34367156; PMCID: PMC8336601.
36. Allers K, Puyskens A, Epple HJ, Schurmann D, Hofmann J, Moos V, Schneider T. The effect of timing of antiretroviral therapy on CD4+ T-cell reconstitution in the intestine of HIV-infected patients. Mucosal Immunol. 2016;9(1):265-74. doi: 10.1038/mi.2015.58. PubMed PMID: 26129649.
37. Sainz T, Serrano-Villar S, Mann S, Ma ZM, Utay NS, Thompson CG, Chun TW, Kashuba AD, Siewe B, Albanese A, Troia-Cancio P, Sinclair E, Somasunderam A, Yotter T, Moreno S, Pollard RB, Landay A, Miller CJ, Asmuth DM. Delayed gastrointestinal-associated lymphoid tissue reconstitution in duodenum compared with rectum in HIV-infected patients initiating antiretroviral therapy. AIDS. 2019;33(15):2289-98. doi: 10.1097/QAD.0000000000002361. PubMed PMID: 31764094; PMCID: PMC6905119.
38. Giorgi JV, Ho HN, Hirji K, Chou CC, Hultin LE, O’Rourke S, Park L, Margolick JB, Ferbas J, Phair JP. CD8+ lymphocyte activation at human immunodeficiency virus type 1 seroconversion: development of HLA-DR+ CD38- CD8+ cells is associated with subsequent stable CD4+ cell levels. The Multicenter AIDS Cohort Study Group. J Infect Dis. 1994;170(4):775-81. doi: 10.1093/infdis/170.4.775. PubMed PMID: 7930717.
39. Asmuth DM, Pinchuk IV, Wu J, Vargas G, Chen X, Mann S, Albanese A, Ma ZM, Saroufeem R, Melcher GP, Troia-Cancio P, Torok NJ, Miller CJ, Powell DW. Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy. AIDS. 2015;29(8):877-88. doi: 10.1097/QAD.0000000000000636. PubMed PMID: 25784439; PMCID: PMC4520701.
40. Nielsen MM, Witherden DA, Havran WL. gammadelta T cells in homeostasis and host defence of epithelial barrier tissues. Nat Rev Immunol. 2017;17(12):733-45. doi: 10.1038/nri.2017.101. PubMed PMID: 28920588; PMCID: PMC5771804.
41. Walker EM, Slisarenko N, Gerrets GL, Grasperge BF, Mattison JA, Kissinger PJ, Welsh DA, Veazey RS, Jazwinski SM, Rout N. Dysregulation of IL-17/IL-22 Effector Functions in Blood and Gut Mucosal Gamma Delta T Cells Correlates With Increase in Circulating Leaky Gut and Inflammatory Markers During cART-Treated Chronic SIV Infection in Macaques. Front Immunol. 2021;12:647398. doi: 10.3389/fimmu.2021.647398. PubMed PMID: 33717202; PMCID: PMC7946846.
42. Schnell A, Littman DR, Kuchroo VK. T(H)17 cell heterogeneity and its role in tissue inflammation. Nat Immunol. 2023;24(1):19-29. doi: 10.1038/s41590-022-01387-9. PubMed PMID: 36596896; PMCID: PMC10795475.
43. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6(4):353-60. doi: 10.1038/ni1181. PubMed PMID: 15785761.
44. Yero A, Farnos O, Rabezanahary H, Racine G, Estaquier J, Jenabian MA. Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection. J Virol. 2019;93(19). doi: 10.1128/JVI.00371-19. PubMed PMID: 31315987; PMCID: PMC6744245.
45. Sereti I, Verburgh ML, Gifford J, Lo A, Boyd A, Verheij E, Verhoeven A, Wit F, Schim van der Loeff MF, Giera M, Kootstra NA, Reiss P, Vujkovic-Cvijin I. Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV. Cell Rep. 2023;42(11):113336. doi: 10.1016/j.celrep.2023.113336. PubMed PMID: 37918403; PMCID: PMC10872975.
46. Apetrei C, Gaufin T, Brocca-Cofano E, Sivanandham R, Sette P, He T, Sivanandham S, Martinez Sosa N, Martin KJ, Raehtz KD, Kleinman AJ, Valentine A, Krampe N, Gautam R, Lackner AA, Landay AL, Ribeiro RM, Pandrea I. T cell activation is insufficient to drive SIV disease progression. JCI Insight. 2023;8(14). doi: 10.1172/jci.insight.161111. PubMed PMID: 37485874; PMCID: PMC10443804.
47. Schnittman SR, Deitchman AN, Beck-Engeser G, Ahn H, York VA, Hartig H, Hecht FM, Martin JN, Deeks SG, Aweeka FT, Hunt PW. Abnormal Levels of Some Biomarkers of Immune Activation Despite Very Early Treatment of Human Immunodeficiency Virus. J Infect Dis. 2021;223(9):1621-30. doi: 10.1093/infdis/jiaa580. PubMed PMID: 32915986; PMCID: PMC8136975.