Significant Induction of Soluble TNFR2 Compared with TNFR1 in Serum Samples of HIV Patients with or without Antiretroviral Medication

Author(s): Bismark Sarfo*, Zelalem Teka Haile, Selase Deletsu, Eric Akpanja Mensah, Evelyn Yayra Bonney

Journal Name: Infectious Disorders - Drug Targets
Formerly Current Drug Targets - Infectious Disorders

Volume 20 , Issue 2 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Tumor necrosis factor and its receptors (sTNFR1 and sTNFR2) have been implicated in many infectious diseases. Identification of the key receptor (sTNFR1 or sTNFR2) which drives the immunopathogenesis of HIV infection is crucial in developing adjunctive therapy for HIV.

Objective: This study determined the expression levels of sTNFR1 and sTNFR2 in antiretroviral therapy (ART) - experienced and naïve HIV patients.

Methods: A total of 40 HIV patients comprising 30 with ART and 10 without ART were enrolled from the Pantang Hospital located in the Greater Accra Region of Ghana for data and blood collection. Serum concentrations of sTNFR1 and sTNFR2 were determined by ELISA. Mann- Whitney U test was used to examine differences in serum levels of sTNFR1 and sTNFR2 between patients on ART and ART naïve patients. Wilcoxon Signed-Rank test was performed to determine the difference between sTNFR1 and sTNFR2, and Kruskal Wallis test was conducted to compare the effect of different antiretroviral drugs on the levels of sTNFR1 and sTNFR2. P< 0.05 was considered statistically significant.

Results: A Wilcoxon Signed-Ranks Test indicated serum levels of sTNFR2 was statistically significantly higher than sTNFR1 (Z=-5.51; p<0.001). Levels of sTNFR1 and sTNFR2 did not differ by ART status U =91.00 (Z = -1.84), p = 0.065 and U = 131.50 (Z = -0.58, p =0.560), respectively. There were not significant differences in levels of TNFR2 H(2) = 1.86, p=0.395 and sTNFR1 (H (2) = 4.37, p=0.113 across different ART combinations.

Conclusion: Compared to sTNFR1, the level of sTNFR2 is significantly increased during HIV infection irrespective of ART status. The high sTNFR2 level is not associated with antiretroviral drugs and may be another potential target for therapeutic development. This is the first study of sTNFRs in African population.

Keywords: HIV, antiretroviral, TNF receptors, immunopathogenesis, adjunctive therapy, therapeutic development.

[1]
Hunt, P.W. HIV and inflammation: mechanisms and consequences. Curr. HIV/AIDS Rep., 2012, 9(2), 139-147.
[http://dx.doi.org/10.1007/s11904-012-0118-8] [PMID: 22528766]
[2]
Norris, P.J.; Pappalardo, B.L.; Custer, B.; Spotts, G.; Hecht, F.M.; Busch, M.P. Elevations in IL-10, TNF-α, and IFN-γ from the earliest point of HIV Type 1 infection. AIDS Res. Hum. Retroviruses, 2006, 22(8), 757-762.
[http://dx.doi.org/10.1089/aid.2006.22.757] [PMID: 16910831]
[3]
Matsuyama, T.; Kobayashi, N.; Yamamoto, N. Is AIDS a TNF disease?, 2008.
[4]
Kumar, A.; Abbas, W.; Herbein, G. TNF and TNF receptor superfamily members in HIV infection: New cellular targets for therapy? [Internet]. Mediators Inflamm. 2013 [cited 2018 Mar 13].Available from:,, 2013.https://www.hindawi.com/journals/mi/2013/484378/
[5]
Haraguchi, S.; Day, N.K.; Kamchaisatian, W.; Beigier-Pompadre, M.; Stenger, S.; Tangsinmankong, N.; Sleasman, J.W.; Pizzo, S.V.; Cianciolo, G.J. LMP-420, a small-molecule inhibitor of TNF-alpha, reduces replication of HIV-1 and Mycobacterium tuberculosis in human cells. AIDS Res. Ther., 2006, 3, 8.
[http://dx.doi.org/10.1186/1742-6405-3-8] [PMID: 16573838]
[6]
Silva, L.C.; Ortigosa, L.C.; Benard, G. Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy, 2010, 2(6), 817-833.
[http://dx.doi.org/10.2217/imt.10.67] [PMID: 21091114]
[7]
Bailer, R.T.; Lee, B.; Montaner, L.J. IL-13 and TNF-α inhibit dual-tropic HIV-1 in primary macrophages by reduction of surface expression of CD4, chemokine receptors CCR5, CXCR4 and post-entry viral gene expression. Eur. J. Immunol., 2000, 30(5), 1340-1349.
[http://dx.doi.org/10.1002/(SICI)1521-4141(200005)30:5<1340:AID-IMMU1340>3.0.CO;2-L] [PMID: 10820380]
[8]
Kedzierska, K.; Crowe, S.M.; Turville, S.; Cunningham, A.L. The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages. Rev. Med. Virol., 2003, 13(1), 39-56.
[http://dx.doi.org/10.1002/rmv.369] [PMID: 12516061]
[9]
Aggarwal, B.B; Gupta, SC; Kim, JH. Historical perspectives on tumor necrosis factor and its superfamily: twenty-five years later, a golden journey. Blood. 2011;blood, 2011.
[10]
Pasquereau, S. Kumar, A.; Herbein, G.;Targeting TNF and TNF receptor pathway in HIV-1 infection: from immune activation to viral reservoirs. Viruses, 2017, 9, 64.
[http://dx.doi.org/10.3390/v9040064]
[11]
de Oliveira Pinto, L.M.; Garcia, S.; Lecoeur, H.; Rapp, C.; Gougeon, M-L. Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood, 2002, 99(5), 1666-1675.
[http://dx.doi.org/10.1182/blood.V99.5.1666] [PMID: 11861282]
[12]
Hijdra, D.; Vorselaars, A.D.; Grutters, J.C.; Claessen, A.M.; Rijkers, G.T. Differential expression of TNFR1 (CD120a) and TNFR2 (CD120b) on subpopulations of human monocytes. J. Inflamm. (Lond.), 2012, 9(1), 38.
[http://dx.doi.org/10.1186/1476-9255-9-38] [PMID: 23039818]
[13]
Herbein, G.; Gras, G.; Khan, K.A.; Abbas, W. Macrophage signaling in HIV-1 infection. Retrovirology, 2010, 7, 34.
[http://dx.doi.org/10.1186/1742-4690-7-34] [PMID: 20380698]
[14]
Herbein, G.; Khan, K.A. Is HIV infection a TNF receptor signalling-driven disease? Trends Immunol., 2008, 29(2), 61-67.
[http://dx.doi.org/10.1016/j.it.2007.10.008] [PMID: 18178131]
[15]
Wig, N.; Anupama, P.; Singh, S.; Handa, R.; Aggarwal, P.; Dwivedi, S.N.; Jailkhani, B.L.; Wali, J.P. Tumor necrosis factor-α levels in patients with HIV with wasting in South Asia. AIDS Patient Care STDS, 2005, 19(4), 212-215.
[http://dx.doi.org/10.1089/apc.2005.19.212] [PMID: 15857192]
[16]
Aggarwal, B.B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol., 2003, 3(9), 745-756.
[http://dx.doi.org/10.1038/nri1184] [PMID: 12949498]
[17]
Zangerle, R.; Gallati, H.; Sarcletti, M.; Weiss, G.; Denz, H.; Wachter, H.; Fuchs, D. Increased serum concentrations of soluble tumor necrosis factor receptors in HIV-infected individuals are associated with immune activation. J. Acquir. Immune Defic. Syndr., 1994, 7(1), 79-85.
[PMID: 7903382]
[18]
Godfried, M.H.; van der Poll, T.; Jansen, J.; Romijin, J.A.; Schattenkerk, J.K.; Endert, E.; van Deventer, S.J.; Sauerwein, H.P. Soluble receptors for tumour necrosis factor: a putative marker of disease progression in HIV infection. AIDS, 1993, 7(1), 33-36.
[http://dx.doi.org/10.1097/00002030-199301000-00005] [PMID: 8382926]
[19]
Hattori, M.; Tateyama, M.; Oishi, T.; Miyasaka, S.; Fukutake, K. [Serum levels of soluble tumor necrosis factor receptors as markers for disease progression of human immunodeficiency virus infection]. Rinsho Byori, 1997, 45(11), 1085-1090.
[PMID: 9396350]
[20]
Williams, A.S.; Chen, L.; Kasahara, D.I.; Si, H.; Wurmbrand, A.P.; Shore, S.A. Obesity and airway responsiveness: role of TNFR2. Pulm. Pharmacol. Ther., 2013, 26(4), 444-454.
[http://dx.doi.org/10.1016/j.pupt.2012.05.001] [PMID: 22584291]
[21]
Inoue, N.; Watanabe, M.; Nanba, T.; Wada, M.; Akamizu, T.; Iwatani, Y. Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody. Clin. Exp. Immunol., 2009, 156(2), 199-204.
[http://dx.doi.org/10.1111/j.1365-2249.2009.03884.x] [PMID: 19250279]
[22]
Haga, T.; Efird, J.T.; Tugizov, S.; Palefsky, J.M. Increased TNF-alpha and sTNFR2 levels are associated with high-grade anal squamous intraepithelial lesions in HIV-positive patients with low CD4 level. Papillomavirus Res., 2017, 3, 1-6.
[http://dx.doi.org/10.1016/j.pvr.2016.11.003] [PMID: 28720441]
[23]
Leng, S.X.; Dandorf, S.; Li, H.; Carlson, J.; Hui, J.; Mehta, S.H.; Piggott, D.; Islam, S.; Manwani, B.; Kirk, G.D. Associations of circulating soluble tumor necrosis factor-α receptors 1 and 2 with Interleukin-6 levels in an aging cohort of injection drug users with or at high risk for HIV infection. AIDS Res. Hum. Retroviruses, 2015, 31(12), 1257-1264.
[http://dx.doi.org/10.1089/aid.2015.0134] [PMID: 26414536]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 2
Year: 2020
Page: [175 - 181]
Pages: 7
DOI: 10.2174/1871526518666181016110409
Price: $65

Article Metrics

PDF: 17
HTML: 2