Abstract
Background: HIV infection induces alterations in the gut-associated lymphoid tissue (GALT) that constitutes the most important site for viral replication due to the extensive presence of effector memory T-cells. In the case of HIV-controllers, several studies have reported fewer peripheral alterations and conserved immune responses that correlate with viral control; however, the histopathological characterization of GALT in those patients is still missing. In this study, we evaluated pathological alterations in GALT, trying to associate them with clinical parameters of HIV infected patients with or without evidence of viral control.
Methods: This study included eight HIV-controllers (antiretroviral treatment-naïve patients, with viral loads below 2.000 copies/mL for at least 1 year); 14 Noncontrollers (antiretroviral treatmentnaïve patients, with viral loads > 2.000 copies/mL and CD4+ T cells count > 250 cells/μL), and 12 uninfected donors.
Biopsy fragments were obtained by rectosigmoidoscopy and stained with hematoxylin and eosin, silver methenamine, Ziehl Neelsen, and modified Ziehl Neelsen.
Results: Histopathological findings in HIV-controllers were similar to those observed in the uninfected group. In contrast, noncontrollers exhibited several alterations including condyloma acuminate, squamous metaplasia and acute colitis. These alterations were associated with disease progression.
Conclusion: HIV-controllers exhibit lower pathological alterations in the gut tissue, associated with higher CD4 T cell count, and lower viral load.
Keywords: HIV-controllers, Noncontrollers, GALT, histopathological alterations, CD4+ T cells, rectosigmoidoscopy.
Graphical Abstract
[1]
Schenk M, Mueller C. The mucosal immune system at the gastrointestinal barrier. Best Pract Res Clin Gastroenterol 2008; 22(3): 391-409.
[2]
Ivanov II, Diehl GE, Littman DR. Lymphoid tissue inducer cells in intestinal immunity. Curr Top Microbiol Immunol 2006; 308: 59-82.
[3]
Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200(6): 749-59.
[4]
Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. Aids 2003; 17(13): 1881-8.
[5]
Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12(12): 1365-71.
[6]
Kotler DP, Gaetz HP, Lange M, Klein EB, Holt PR. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984; 101(4): 421-8.
[7]
Maidji E, Somsouk M, Rivera JM, Hunt PW, Stoddart CA. Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction. PLoS Pathog 2017; 13(2): e1006202.
[8]
Simonsen M, Nahas SC, da Silva Filho EV, Araújo SEA, Kiss DR, Nahas CSR. Atypical Perianal Herpes Simplex Infection in HIV-Positive Patients. Clinics 2008; 63(1): 143-6.
[9]
Machalek DA, Poynten M, Jin F, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol 2012; 13(5): 487-500.
[10]
Mendez-Martinez R, Rivera-Martinez NE, Crabtree-Ramirez B, et al. Multiple human papillomavirus infections are highly prevalent in the anal canal of human immunodeficiency virus-positive men who have sex with men. BMC Infect Dis 2014; 14: 671.
[11]
Walker BD. Elite control of HIV Infection: implications for vaccines and treatment. Top HIV Med 2007; 15(4): 134-6.
[12]
Gonzalez SM, Taborda NA, Correa LA, et al. Particular activation phenotype of T cells expressing HLA-DR but not CD38 in GALT from HIV-controllers is associated with immune regulation and delayed progression to AIDS. Immunol Res 2016; 64(3): 765-74.
[13]
Pereyra F, Addo MM, Kaufmann DE, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 2008; 197(4): 563-71.
[14]
Rueda CM, Velilla PA, Chougnet CA, Montoya CJ, Rugeles MT. HIV-Induced T-Cell Activation/Exhaustion in Rectal Mucosa Is Controlled Only Partially by Antiretroviral Treatment. PLoS One 2012; 7(1): 1-9.
[15]
Havlir DV, Bassett R, Levitan D, et al. Prevalence and predictive value of intermittent viremia with combination hiv therapy. JAMA 2001; 286(2): 171-9.
[16]
Ko CW, Dominitz JA. Complications of colonoscopy: magnitude and management. Gastrointest Endosc Clin N Am 2010; 20(4): 659-71.
[17]
Feria MG, Taborda NA, Hernandez JC, Rugeles MT. HIV replication is associated to inflammasomes activation, IL-1beta, IL-18 and caspase-1 expression in GALT and peripheral blood. PLoS One 2018; 13(4): e0192845.
[18]
Gonzalez SM, Taborda NA, Feria MG, et al. High Expression of Antiviral Proteins in Mucosa from Individuals Exhibiting Resistance to Human Immunodeficiency Virus. PLoS One 2015; 10(6): e0131139.
[19]
Rios CM, Velilla PA, Rugeles MT. Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells. Open Virol J 2012; 6: 49-58.
[20]
Shaw JM, Hunt PW, Critchfield JW, et al. Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers. J Virol 2011; 85(21): 11422-34.
[21]
Taborda NA, González SM, Alvarez CM, Correa LA, Montoya CJ, Rugeles MT. Higher Frequency of NK and CD4+ T-Cells in Mucosa and Potent Cytotoxic Response in HIV Controllers. PLoS One 2015; 10(8): e0136292.
[22]
Niv G, Grinberg T, Dickman R, Wasserberg N, Niv Y. Perforation and mortality after cleansing enema for acute constipation are not rare but are preventable. Int J Gen Med 2013; 6: 323-8.
[23]
Taborda NA, Gonzalez SM, Correa LA, Montoya CJ, Rugeles MT. Spontaneous HIV Controllers Exhibit Preserved Immune Parameters in Peripheral Blood and Gastrointestinal Mucosa. J Acquir Immune Defic Syndr 2015; 70(2): 115-21.
[24]
Keating J, Bjarnason I, Somasundaram S, et al. Intestinal absorptive capacity, intestinal permeability and jejunal histology in HIV and their relation to diarrhoea. Gut 1995; 37(5): 623-9.
[25]
Cummins AG, LaBrooy JT, Stanley DP, Rowland R, Shearman DJ. Quantitative histological study of enteropathy associated with HIV infection. Gut 1990; 31(3): 317-21.
[26]
McGowan I, Elliott J, Fuerst M, et al. Increased HIV-1 mucosal replication is associated with generalized mucosal cytokine activation. J Acquir Immune Defic Syndr 2004; 37(2): 1228-36.
[27]
Hatano H, Somsouk M, Sinclair E, et al. Comparison of HIV DNA and RNA in Gut-Associated Lymphoid Tissue of HIV-Infected Controllers and Non-controllers. AIDS 2013; 27(14): 2255-60.
[28]
van Marle G, Church DL, van der Meer F, Gill MJ. Combating the HIV reservoirs. Biotechnol Genet Eng Rev 2018; 34(1): 76-89.
[29]
Pasquereau S, Kumar A, Abbas W, Herbein G. Counteracting Akt Activation by HIV Protease Inhibitors in Monocytes/Macrophages. Viruses 2018; 10(4): pii: E190.
[30]
Kumar A, Abbas W, Bouchat S, et al. Limited HIV-1 Reactivation in Resting CD4(+) T cells from Aviremic Patients under Protease Inhibitors. Sci Rep 2016; 6: 38313.
[31]
Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013; 5(193): 193ra91.
[32]
Nowak P, Troseid M, Avershina E, et al. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS 2015; 29(18): 2409-18.
[33]
Serrano-Villar S, Rojo D, Martinez-Martinez M, et al. HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases. Sci Rep 2016; 6: 26192.
[34]
Ji Y, Zhang F, Zhang R, et al. Changes in intestinal microbiota in HIV-1-infected subjects following cART initiation: influence of CD4+ T cell count. Emerg Microbes Infect 2018; 7(1): 113.
[35]
Cassol E, Rossouw T, Malfeld S, et al. CD14(+) macrophages that accumulate in the colon of African AIDS patients express pro-inflammatory cytokines and are responsive to lipopolysaccharide. BMC Infect Dis 2015; 15: 430.
[36]
Mait-Kaufman J, Fakioglu E, Mesquita PM, Elliott J, Lo Y, Madan RP. Chronic HIV infection is associated with upregulation of proinflammatory cytokine and chemokine and alpha defensin gene expression in colorectal mucosa. AIDS Res Hum Retroviruses 2015; 31(6): 615-22.
[37]
Allers K, Fehr M, Conrad K, et al. Macrophages accumulate in the gut mucosa of untreated HIV-infected patients. J Infect Dis 2014; 209(5): 739-48.
[38]
Maingat F, Halloran B, Acharjee S, et al. Inflammation and epithelial cell injury in AIDS enteropathy: involvement of endoplasmic reticulum stress. Faseb J 2011; 25(7): 2211-20.
[39]
Taborda NA, Hernandez JC, Lajoie J, et al. Short communication: low expression of activation and inhibitory molecules on NK cells and CD4(+) T cells is associated with viral control. AIDS Res Hum Retroviruses 2015; 31(6): 636-40.
[40]
Talal AH, Irwin CE, Dieterich DT, Yee H, Zhang L. Effect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue. J Acquir Immune Defic Syndr 2001; 26(3): 208-17.
[41]
Brandt L, Benfield T, Mens H, et al. Low level of regulatory T cells and maintenance of balance between regulatory T cells and TH17 cells in HIV-1-infected elite controllers. J Acquir Immune Defic Syndr 2011; 57(2): 101-8.
[42]
Leeansyah E, Ganesh A, Quigley MF, et al. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood 2013; 121(7): 1124-35.
[43]
Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997; 337(15): 1029-35.
[44]
Heise C, Dandekar S, Kumar P, Duplantier R, Donovan RM, Halsted CH. Human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal mucosa. Gastroenterology 1991; 100(6): 1521-7.
[45]
Assimakopoulos SF, Dimitropoulou D, Marangos M, Gogos CA. Intestinal barrier dysfunction in HIV infection: pathophysiology, clinical implications and potential therapies. Infection 2014; 42(6): 951-9.
[46]
Batman PA, Kapembwa MS, Belmonte L, et al. HIV enteropathy: HAART reduces HIV-induced stem cell hyperproliferation and crypt hypertrophy to normal in jejunal mucosa. J Clin Pathol 2014; 67(1): 14-8.
[47]
Oktedalen O, Skar V, Dahl E, Serck-Hanssen A. Changes in small intestinal structure and function in HIV-infected patients with chronic diarrhoea. Scand J Infect Dis 1998; 30(5): 459-63.
[48]
Marquez-Coello M, Montes-de-Oca Arjona M, Fernandez-Gutierrez Del Alamo C, Ruiz-Sanchez C, Giron-Gonzalez JA. Peripheral Th17 cells expressing beta7 intestinal homing receptor in recent and chronic HIV infections. Clin Exp Immunol 2018; 194(3): 350-60.
[49]
Hensley-McBain T, Berard AR, Manuzak JA, et al. Intestinal damage precedes mucosal immune dysfunction in SIV infection. Mucosal Immunol 2018; 11(5): 1429-40.
[50]
Loiseau C, Requena M, Mavigner M, et al. CCR6(-) regulatory T cells blunt the restoration of gut Th17 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals. Mucosal Immunol 2016; 9(5): 1137-50.
[51]
Ryan ES, Micci L, Fromentin R, et al. Loss of function of intestinal IL-17 and IL-22 producing cells contributes to inflammation and viral persistence in SIV-infected rhesus macaques. PLoS Pathog 2016; 12(2): e1005412.
[52]
d’Ettorre G, Ceccarelli G, Andreotti M, et al. Analysis of Th17 and Tc17 frequencies and antiviral defenses in gut-associated lymphoid tissue of chronic HIV-1 positive patients. Mediators Inflamm 2015; 2015: 395484.
[53]
Stanley MA. Epithelial cell responses to infection with human papillomavirus. Clin Microbiol Rev 2012; 25(2): 215-22.
[54]
Quinlan JM, Colleypriest BJ, Farrant M, Tosh D. Epithelial metaplasia and the development of cancer. Biochim Biophys Acta 2007; 1776(1): 10-21.
[55]
Okamoto R, Watanabe M. Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease. J Gastroenterol 2016; 51(1): 11-21.
[56]
Kayamba V, Shibemba A, Zyambo K, Heimburger DC, Morgan DR, Kelly P. High prevalence of gastric intestinal metaplasia detected by confocal laser endomicroscopy in Zambian adults. PLoS One 2017; 12(9): e0184272.
[57]
Barling DR, Tucker S, Varia H, Isaacs P. Large bowel perforation secondary to CMV colitis: an unusual primary presentation of HIV infection. BMJ Case Rep 2016; 2016: pii: bcr2016217221.
[58]
Fazendin EA, Crean AJ, Fazendin JM, et al. Condyloma Acuminatum, Anal Intraepithelial Neoplasia, and Anal Cancer in the Setting of HIV: Do We Really Understand the Risk? Dis Colon Rectum 2017; 60(10): 1078-82.
[59]
Furukawa S, Uota S, Yamana T, et al. Distribution of Human Papillomavirus Genotype in Anal Condyloma Acuminatum Among Japanese Men: The Higher Prevalence of High Risk Human Papillomavirus in Men Who Have Sex with Men with HIV Infection. AIDS Res Hum Retroviruses 2018; 34(4): 375-81.
[60]
Pudney J, Wangu Z, Panther L, et al. Condylomata acuminata (anogenital warts) contain accumulations of HIV-1 target cells that may provide portals for HIV transmission. J Infect Dis 2019; 219(2): 275-83.
[61]
Singh DK, Anastos K, Hoover DR, et al. Human Papillomavirus Infection and Cervical Cytology in HIV-Infected and HIV-Uninfected Rwandan Women. J Infect Dis 2009; 199(12): 1851.
[62]
Brickman C, Palefsky JM. Human papillomavirus in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era. Curr HIV/AIDS Rep 2015; 12(1): 6-15.
[63]
Schwartz LM, Castle PE, Follansbee S, et al. Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men. J Infect Dis 2013; 208(11): 1768-75.
[64]
Medina-Laabes DT, Suarez-Perez EL, Guiot HM, et al. Human papillomavirus correlates with histologic anal high-grade squamous intraepithelial lesions in hispanics with HIV. J Low Genit Tract Dis 2018; 22(4): 320-5.
[65]
Kuri-Cervantes L, de Oca GS, Avila-Rios S, Hernandez-Juan R, Reyes-Teran G. Activation of NK cells is associated with HIV-1 disease progression. J Leukoc Biol 2014; 96(1): 7-16.
[66]
Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197(1): 126-33.
[67]
Skowyra A, Mikuła T, Suchacz M, Skowyra A, Wiercińska-Drapało A. The role of serum I-FABP concentration in assessment of small intestine mucosa among HIV-infected patients. Eur J Inflamm 2015; 13(2): 75-81.
[68]
Dinh DM, Volpe GE, Duffalo C, et al. Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. J Infect Dis 2015; 211(1): 19-27.
[69]
Kristoff J, Haret-Richter G, Ma D, et al. Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication. J Clin Invest 2014; 124(6): 2802-6.
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