Alteraciones en la producción de citocinas en respuesta a Toxoplasma gondii aparecen desde las etapas tempranas en pacientes co-infectados con VIH-1.

Alterations in the production of cytokines in response to Toxoplasma gondii appear from early stages in patients co-infected with HIV-1.

Palabras clave: VIH-1, Toxoplasma gondii, respuesta inmunitaria, co-infección


Tanto el Virus de Inmunodeficiencia Humana-1 (VIH-1), como el protozoo Toxoplasma gondii son capaces de infectar al ser humano e invadir su sistema nervioso central (SNC). En individuos inmunocompetentes T. gondii causa infecciones crónicas, generalmente asintomáticas; sin embargo, la inmunodeficiencia asociada a etapas avanzadas de la infección por VIH-1, se relaciona con la pérdida del control de la infección parasitaria latente y enfermedades graves a nivel del SNC, como encefalitis toxoplásmica. Este trabajo tuvo como objetivo evaluar la evolución de la respuesta inmunitaria contra T. gondii en pacientes co-infectados con VIH-1, en distintas etapas de la infección viral. La respuesta contra T. gondii se evaluó a través de la producción in vitro de citocinas en respuesta a antígenos parasitarios, en individuos con serología positiva para VIH-1 y negativa para T. gondii (P1), positiva para VIH-1 y T. gondii (P2), negativa para VIH-1 y T. gondii (C1) y negativa para VIH-1 y positiva para T. gondii (C2). Los pacientes (P1 y P2) se agruparon en tempranos/asintomáticos (P1A, P2A) o tardíos/sintomáticos (P1B/C, P2B/C) de acuerdo a su recuento de linfocitos T CD4+ en sangre periférica (>350 o <350 células/μL, respectivamente). La infección por VIH-1, desde etapas tempranas, se asoció con una producción de IL-2, TNF-α e IFN-γ en respuesta a T. gondii significativamente menor. Estos defectos pueden entorpecer la respuesta anti-T. gondii en pacientes co-infectados, aumentando la posibilidad de reactivación de las infecciones latentes, lo que representa un riesgo para la integridad y funcionalidad del SNC.


La descarga de datos todavía no está disponible.

Biografía del autor/a

Edwin Escobar-Guevara, Universidad Central de Venezuela, Caracas, Venezuela.

Laboratorio de Inmunofisiología Celular, Escuela de Medicina “José María Vargas”, Universidad Central de Venezuela, Caracas, Venezuela.

María de Quesada-Martínez, Universidad Central de Venezuela, Caracas, Venezuela.

Cátedra de Fisiopatología, Escuela de Medicina “José María Vargas”, Universidad Central de Venezuela, Caracas, Venezuela.

Yhajaira Roldán-Dávila, Hospital “José Ignacio Baldó”, El Algodonal, Caracas.

Servicio de Infectología, Hospital “José Ignacio Baldó”, El Algodonal, Caracas.

Belkisyolé Alarcón de Noya , Universidad Central de Venezuela, Caracas, Venezuela.

Sección de Inmunología, Instituto de Medicina Tropical, Universidad Central de Venezuela, Caracas, Venezuela.

Miguel Alfonzo-Díaz, Universidad Central de Venezuela, Caracas, Venezuela.

Laboratorio de Inmunofisiología Celular, Escuela de Medicina “José María Vargas”, Universidad Central de Venezuela, Caracas, Venezuela.


Ferguson DJP. Toxoplasma gondii: 1908-2008, homage to Nicolle, Manceaux and Splendore. Mem Inst Oswaldo Cruz 2009; 104(2): 133-148.

Molan A, Nosaka K, Hunter M, Wang W. Global status of Toxoplasma gondii infection: systematic review and prevalence snapshots. Trop Biomed 2019; 36(4): 898–925.

Remington JS, Cavanaugh EN. Isolation of the encysted form of Toxoplasma gondii from human skeletal muscle and brain. N Engl J Med 1965; 273(24):1308-10.

Carruthers VB, Suzuki Y. Effects of Toxoplasma gondii infection on the brain. Schizophr Bull 2007; 33(3):745-751.

Dubey JP, Lindsay DS, Speer CA. Structures of Toxoplasma gondii tachyzoites, brad-yzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev 1998; 11(2):267-299.

Suzuki Y. Immunopathogenesis of Cerebral Toxoplasmosis. J Infect Dis 2002; 186(Suppl 2):S234–240.

Ghatak NR, Sawyer DR. A morphologic study of opportunistic cerebral toxoplasmosis. Acta Neuropathol 1978; 42(3): 217-221.

Halonen SK, Lyman WD, Chiu FC. Growth and development of Toxoplasma gondii in human neurons and astrocytes. J Neuro-pathol Exp Neurol 1996; 55(11):1150-1156.

Yarovinsky F. Innate immunity to Toxoplasma gondii infection. Nat Rev Immunol 2014; 14:109–121.

Lopez-Yglesias AH, Burger E, Camanzo E, Martin AT, Araujo AM, Kwok SF, Yarovinsky F. T-bet dependent ILC1- and NK cell-derived IFN-γ mediates cDC1-dependent host resistance against Toxoplasma gondii. PLoS Pathog 2021; 17(1): e1008299.

Gazzinelli RT, Hakim FT, Hieny S, Shearer GM, Sher A. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol 1991; 146(1):286-292.

Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to re-activate chronic infection with Toxoplasma gondii. J Immunol 1992; 149(1):175-180.

Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science 1988; 240(4851):516-518.

Langermans JA, Van der Hulst ME, Nibbering PH, Hiemstra PS, Fransen L, Van Furth R. IFN-gamma-induced L -arginine- dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-alpha. J Immunol 1992; 148(2):568-574.

Gazzinelli RT, Eltoum I, Wynn TA, Sher A. Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down- regulated expression of inducible nitric oxide synthase and other markers of macrophage activation. J Immunol 1993; 151(7):3672-3681.

Bohne W, Heesemann J, Gross U. Reduced replication of Toxoplasma gondii is necessary for induction of bradyzoite-specific antigens: a possible role for nitric oxide in triggering stage conversion. Infect Immun 1994; 62(5):1761-1767.

Suzuki Y, Conley FK, Remington JS. Importance of endogenous IFN-gamma for prevention of toxoplasmic encephalitis in mice. J Immunol 1989; 143(6):2045-2050.

Wang X, Kang H, Kikuchi T, Suzuki Y. Gamma interferon production, but not perfor inmediated cytolytic activity, of T cells is required for prevention of toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease. Infect Immun 2004; 72(8):4432-4438.

Sturge CR, Felix Yarovinsky F. Complex immune cell interplay in the gamma interferon response during Toxoplasma gondii infection. Infect Immun 2014; 82(8):3090–3097.

Kang H, Suzuki Y. Requirement of non-T cells that produce gamma interferon for prevention of reactivation of Toxoplasma gondii infection in the brain. Infect Immun 2001; 69(5):2920-2927.

Kupz A, Pai S, Giacomin PR, Whan JA, Walker RA, Hammoudi PM, Smith NC, Miller CM. Treatment of mice with S4B6 IL -2 complex prevents lethal toxoplasmosis via IL -12- and IL -18-dependent interferon-gamma production by non-CD4 immune cells. Sci Rep 2020; 10(1):13115.

Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kühn R, Müller W, Trinchieri G, Sher A. In the absence of endogenous IL -10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL -12, IFN-gamma and TNF-alpha. J Immunol 1996; 157(2):798-805.

Wilson EH, Wille-Reece U, Dzierszinski F, Hunter CA. A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis. J Neuroimmunol 2005; 165(1):63-74.

Wang ZD, Liu HH, Ma ZX, Ma HY, Li ZY, Yang ZB, Zhu XQ, Xu B, Wei F, Liu Q. Toxoplasma gondii infection in immunocom-promised patients: A systematic review and meta-analysis. Front Microbiol 2017; 8:389.

Wong SY, Remington JS. Biology of Toxoplasma gondii. AIDS 1993; 7(3):299-316.

Luft BJ, Remington JS. AIDS commentary. Toxoplasmic encephalitis. J Infect Dis 1988; 157:1-6.

Boasso A, Shearer GM, Chougnet C. Immune dysregulation in human immuno- deficiency virus infection: know it, fix it, prevent it? J Intern Med 2009; 265(1):78- 96.

De Boer RJ. Time scales of CD4+ T cell depletion in HIV infection. PLoS Med 2007; 4(5):e193.

Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA, Herzenberg LA. CD8 naïve cell counts decrease progressively in HIV-infected adults. J Clin Invest 1995; 95:2061-2066.

Denkers EY, Gazzinelli RT. Regulation and function of T-cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev 1998; 11(4): 569-588.

Yap GS, Sher A. Cell-mediated immunity to Toxoplasma gondii: initiation, regulation and effector function. Immunobiology 1999; 201(2):240-247.

Tait ED, Christopher A, Hunter CA. Advances in understanding immunity to Toxoplasma gondii. Mem Inst Oswaldo Cruz 2009; 104(2):201-210.

Sasai M, Pradipta A, Yamamoto M. Host immune responses to Toxoplasma gondii. Int Immunol 2018; 30(3):113–119.

Fisch D, Clough B, Frickel EM. Human immunity to Toxoplasma gondii. PLoS Pathog 2019; 15(12): e1008097.

MacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol 2012; 12(5):367-82.

Randow F, MacMicking JD, James LC. Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 2013; 340(6133):701-706.

Chao CC, Gekker G, Hu S, Peterson PK. Human microglial cell defense against Toxoplasma gondii. The role of cytokines. J Immunol 1994; 152(3):1246-1252.

Däubener W, Remscheid C, Nockemann S, Pilz K, Seghrouchni S, Mackenzie C, Hadding U. Anti-parasitic effector mechanisms in human brain tumor cells: role of interferon-gamma and tumor necrosis factor-alpha. Eur J Immunol 1996; 26(2):487-492.

Janssen R, van Wengen A, Verhard E, De Boer T, Zomerdijk T, Ottenhoff THM, Van Dissel JT. Divergent role for TNF-α in IFN- γ-induced killing of Toxoplasma gondii and Salmonella typhimurium contributes to se- lective susceptibility in patients with partial IFN-γ receptor 1 deficiency. J Immunol 2002; 169(7):3900-3907.

Ross SH, Cantrell DA. Signaling and function of IL -2 in T lymphocytes. Annu Rev Immunol 2018; 36:411-433.

Bachmann MF, Oxenius A. Interleukin 2: from immunostimulation to immunoregulation and back again. EMBO Rep 2007; 8(12):1142-1148.

Escobar Guevara EE, Alfonzo Díaz MA, Fernández-Mestre M, Camacho Velásquez JC, Roldán Dávila YB, Alarcón de Noya B, De Quesada ME. HIV/Toxoplasma gondii co-infected patients produce lower levels of IFN-γ in response to T. gondii anti-gens, even in the asymptomatic stage of viral infection. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town 2009; Abstract no. WELBA104. ( pa geId=11&abstractId=200722748).

Escobar-Guevara EE, Alfonzo-Díaz MA, Camacho-Velásquez JC, Roldán-Dávila YB, Alarcón de Noya B. HIV/Toxoplasma gondii coinfected patients modify their IL-2 and IL- 10 production in response to T. gondii and HIV antigens, even in the early stage of viral infection. 9th Latin American Congress of Immu- nology, Chile 2009; Abstract No. 354.

De Quesada ME, Marín H, Fuentes Alvarado YJ, Escobar Guevara EE, Roldán Dávila YB, Alfonzo Díaz MA. Disorders on attention, short-term memory and executive functions in HIV/Toxoplasma gondii co-infected patients, in the asymptomatic stage of viral infection. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Rome 2011; Abstract no. CDB224. ( pa geId=11&abstractId=200742783).

De Quesada ME, Fuentes Alvarado YJ, Marín H, Escobar Guevara EE, Roldán Dávila YB, Alfonzo Díaz MA. Visual and auditory event related potentials in HIV/Toxoplasma gondii co-infected patients, in the asymptomatic stage of viral infection. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Rome 2011; Abstract no. CDB225. (http:// pageId=11& abstractId=200742799).

Sternberg S. High-speed scanning in human memory. Science 1966; 153: 652-654.

Sternberg S. In defence of high-speed memory scanning. Q J Exp Psychol 2016; 69(10):2020-2075.

Picton TW. The P300 wave of the human event related potencial. Clin Neurophysiol 1992; 1030 9(1):456-479.

Polich J. P300 clinical utility and control of variability. J Clin Neurophysiol 1998; 15(1):14-33.

Berg EA. A simple objective technique for measuring flexibility in thinking. J Gen Psychol 1948; 39:15-22.

Grant DA, Berg EA. A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J Exp Psychol 1948; 38: 404-411.

Gabuzda DH, Hirsch MS. Neurologic manifestations of infection with human immunodeficiency virus. Clinical features and pathogenesis. Ann Intern Med 1987; 107(3):383-391.

González-Scarano F, Martín-García J. The neuropathogenesis of AIDS. Nat Rev Immunol 2005; 5: 69-81.

Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19:683-765.

Couper KN, Blount DG, Riley EM. IL -10: the master regulator of immunity to infection. J Immunol 2008; 180(9):5771-5777.

Brockman MA, Kwon DS, Tighe DP, Pavlik DF, Rosato PC, Sela J, Porichis F, Le Gall S, Waring MT, Moss K, Jessen H, Pereyra F, Kavanagh DG, Walker BD, Kaufmann DE. IL -10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood. 2009; 114(2):346-356.

Bahraoui E, Briant L, Chazal N. E5564 inhibits immunosuppressive cytokine IL -10 induction promoted by HIV-1 Tat protein. Virol J 2014, 11:214.

Clerici, M, Wynn TA, Berzofsky JA, Blatt SP, Hendrix CW, Sher A, Coffman RL, Shearer GM. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Investig 1994; 93:768-775.

Taoufik Y, Lantz O, Wallon C, Charles A, Dussaix E, Delfraissy JF. Human immunodeficiency virus gp120 inhibits interleukin-12 secretion by human monocytes: an indirect interleukin-10-mediated effect. Blood 1997: 89(8):2842-2848.

Andrade RM, Lima PG, Filho RG, Hygino J, Milczanowski SF, Andrade AF, Lauria C, Brindeiro R, Tanuri A, Bento CA. Interleukin-10-secreting CD4 cells from aged patients with AIDS decrease ivitro HIV replication and tumour necrosis factor alpha production. AIDS 2007; 21(13):1763-1770.

Bento CA, Hygino J, Andrade RM, Saramago CS, Silva RG, Silva AA, Linhares UC, Brindeiro R, Tanuri A, Rosenzwajg M, Klatzmann D, Andrade AF. IL -10-secreting T cells from HIV-infected pregnant women downregulate HIV-1 replication: effect enhanced by antiretroviral treatment. AIDS 2009; 23(1):9-18.

Arias JF, Nishihara R, Bala M, Ikuta K. High systemic levels of interleukin-10, interleukin-22 and Creactive protein in Indian patients are associated with low in vitro replication of HIV-1 subtype C viruses. Retrovirol 2010; 7:15.

Kwon DS, Kaufmann DE. Protective and detrimental roles of IL-10 in HIV pathogenesis. Eur Cytokine Netw 2010; 21:208–214.

Fourman LT, Saylor CF, Cheru L, Fitch K, Looby S, Keller K, Robinson JA, Hoffmann U, Lu MT, Burdo T, Lo J. Anti-inflammatory interleukin 10 inversely relates to coronary atherosclerosis in persons with human immunodeficiency virus. J Infect Dis 2020; 221:510–515.

Islam H, Chamberlain TC, Mui AL, Little JP. Elevated interleukin-10 levels in COVID-19: Potentiation of pro-inflammatory responses or impaired anti-inflammatory action? Front Immunol 2021; 12:677008.

Lu L, Zhang H, Dauphars DJ, He Y-W. A potential role of interleukin 10 in COVID-19 pathogenesis. Trends Immunol 2021; 42:3–5.

Barry JC, Shakibakho S, Durrer C, Simtchouk S, Jawanda KK, Cheung ST, Mui AL, Little JP. Hyporesponsiveness to the anti-inflammatory action of interleukin-10 in Type 2 Diabetes. Sci Rep 2016; 6:21244.

Escobar-Guevara E, Alfonzo-Díaz M. HIV induces a pro-inflammatory/neurotoxic response in primary cultures of nervous cells, even without infection. Symposium “30 Years of HIV Science: Imagine the Future”, Institute Pasteur, 2013; Abstract No. 70/14PS. (http:// HIV2013-Abstract-book.pdf).

Escobar EE, Alfonzo MA. A more pro-inflammatory environment is generated in nervous cells cultures in the simultaneous presence of HIV-1 and Toxoplasma gondii, even with a lower parasite replication. Front Immunol 2013; Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01122. ( conf. fimmu.2013.02.01122/event_abstract)

Landay AL, Clerici M, Hashemi F, Kessler H, Berzofsky JA, Shearer GM. In vitro restoration of T cell immune function in human immunodeficiency virus-positive persons: effects of interleukin (IL)-12 and anti-IL -10. J Infect Dis 1996; 173:1085-1091.

Porichis F, Hart MG, Zupkosky J, Barblu L, Kwon DS, McMullen A, Brennan T, Ahmed R, Freeman GJ, Kavanagh DG, Kaufmann DE. Differential impact of PD-1 and/ or interleukin-10 blockade on HIV-1- specific CD4 T cell and antigen-presenting cell functions. J Virol 2014; 88(5):2508–2518.

Sojka DK, Bruniquel D, Shwartz RH, Singh NJ. IL -2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J Immunol 2004; 172(10):6136-6143.

Dickerson F, Boronow J, Stallings C, Origoni A, Yolken R. Toxoplasma gondii in individuals with schizophrenia: association with clinical and demographic factors and with mortality. Schizophr Bull 2007; 33(3):737-740.

Flegr J. Effects of toxoplasma on human behavior. Schizophr Bull 2007; 33(3):757-760.

Flegr J. How and why toxoplasma makes us crazy. Trends Parasitol 2013; 29:156–163.

Milne G, Webster JP, Walker M. Toxoplasma gondii: An Underestimated Threat? Trends Parasitol 2020; 36(12): 959-969.

Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, Walot I, Miller EN. Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurol 1999; 53(4):782-789.

Selnes OA. Memory loss in persons with HIV/AIDS: assessment and strategies for coping. AIDS Read 2005; 15(6):289-292, 294.

Wright MJ, Woo E, Foley J, Ettenhofer ML, Cottingham ME, Gooding AL, Jang J, Kim MS, Castellon SA, Miller EN, Hinkin CH. Antiretroviral adherence and the nature of HIV-associated verbal memory impairment. J Neuropsychiatry Clin Neurosci 2011; 23(3): 324–331.
Cómo citar
Escobar-Guevara, E., de Quesada-Martínez, M., Roldán-Dávila, Y., Alarcón de Noya , B., & Alfonzo-Díaz, M. (2022). Alteraciones en la producción de citocinas en respuesta a Toxoplasma gondii aparecen desde las etapas tempranas en pacientes co-infectados con VIH-1.: Alterations in the production of cytokines in response to Toxoplasma gondii appear from early stages in patients co-infected with HIV-1. Investigación Clínica, 63(3), 218-234.
Trabajos Originales