Mathews Journal of Immunology & Allergy


Previous Issues Volume 3, Issue 2 - 2019

An Opinion About the Importance of MBL in HIV/HHV-8 Coinfection

Viviane Martha Santos de Morais1* and Maria Rosângela Cunha Duarte Coelho1,2

Viviane Martha Santos de Morais1 and Maria Rosângela Cunha Duarte Coelho1,2

1Virology Division, Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco, Recife-PE, Brazil.

2Departament of Physiology and Pharmacology, Center of Biological Sciences, Federal University of Pernambuco, Recife-PE, Brazil.

Corresponding Author: Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, 50670-901, Recife, Pernambuco, Brazil. 

Received Date: Sep 17, 2019 Published Date: Sep 30, 2019

Copyright © 2019 VMS Morais

Citation: de Morais VMS. (2019). An Opinion about the Importance of MBL in HIV/HHV-8 Coinfection. Mathews J Immunol Allergy. 3(2): 9.


The prevalence of human herpesvirus 8 (HHV-8) varies according to different geographic regions and subpopulations [1–3], however, HHV-8 infection has increased in people living with HIV/AIDS (PLHA) compared to HIV negative individuals [4–7].  

Most of the primary infections caused by HHV-8 are asymptomatic, with viral syndrome characterized by fever, fatigue, lymphadenopathy, diarrhea, and skin rash [8]. However, after the emergence of HIV/AIDS there was a higher incidence of diseases associated with HHV-8 infection, in which the main manifestations are from the excess of cytokines, such as Castleman's multicenter disease, and the formation of tumors, as primary effusion lymphoma and Kaposi's sarcoma (KS) [9,10]. HHV-8 is associated with all forms of Kaposi's sarcoma (KS), the classic, endemic, iatrogenic, and epidemic or HIV/AIDS-associated form [6,11,12], being the necessary etiological agent, but insufficient for the development of clinical manifestations[4,5,10].  

With the HIV/AIDS epidemic, the incidence of KS increased dramatically and presented a more aggressive clinical course, with progression to death, due to the spread of lesions to internal organs. Since 1996, combination antiretroviral therapy was used to reverse HIV-associated immunosuppression, reducing the risk of developing KS [2,11,12]. Although the introduction of therapy has largely altered the natural history of HIV infection, KS is still one of the most common malignancies in PLHA [5,10,13].

Therapy reduced the incidence of KS by approximately 80%, as well as the morbidity and mortality caused by this disease, but KS persist more frequent in PLHA than in the general population. The incidence of KS is approximately 1 in 100,000 in the general population, and 1 in 20 PLHA  About 50% of coinfected men who have sex with men develop KS within 5 to 10 years of acquiring coinfection, even in countries where the prevalence of KS is considered low [3,14]. Studies have reported that KS may develop in treated PLHA, with controlled viral load HIV and CD4 T-cell counts greater than 350 cells/mm3, where up to 40% of these patients require antineoplastic chemotherapy in combination with antiretroviral therapy [5,10,13].

Control of HHV-8 infection and early stages of KS development are mediated by innate and adaptive immunity responses [15–18]. In this context, mannose-binding lectin (MBL) plays a key role in innate immune defense of the host as a pattern recognition receptor by binding with high affinity to the patterns of carbohydrate residues present on the surface of viruses or virus-infected cells, especially when humoral immunity is not fully functional, as in immunosuppressed populations [19–21]. Thus, MBL contributes to activation of the complement system lectin pathway in an antibody-independent mechanism, and may promote opsonophagocytosis, modulate inflammation and induce cell lysis [17,21–25].  

MBL protein is comprised of multimers of an identical polypeptide chain comprising four regions, the cysteine-rich N-terminal region, a collagenous domain, a helical spiral hydrophobic region called the neck, and a carbohydrate recognition domain [24,26]. It has the ability to recognize sugar units such as N-acetyl-D-glucosamine, mannose, N-acetyl-manosamine, fucose and glucose, expressed by different microorganisms and structures, and activate the complement system lectin pathway through association with serine proteases MASP-1, MASP-2 and MASP-3 [26–28].  

MBL protein expression is genetically determined and variations in plasma concentrations can also be attributed to MBL2 gene polymorphisms, which may cause defects in the polymerization of the molecule leading to functional deficiency and/or serum levels [26,27,29–33]. Functional deficiency of plasma MBL concentrations has been associated with various infections or progression of clinical manifestations [20,34–38]. Regarding PLHA, research has shown an association between functional deficiency of MBL plasma concentrations and susceptibility to HIV infection, as well as faster disease progression [22,39–42], while other studies have not found this association with infection, HIV viral load or TCD4 count [23,43].  

MBL is known to bind directly to viruses of several families, such as dengue, Ebola, influenza, HIV, among others, and this interaction leads to neutralization by deposition of complement C3 and C4 in the virus, preventing the interaction of the virus with the host cell and leading to further phagocytosis or viral lysis [41,44–47].  

Regarding the Herpesviridae family, MBL has been reported to bind to HHV-2 surface glycoproteins, although it is not specifically known what this structure would be [35]. While cytomegalovirus (CMV) has glycoproteins that are potential targets for MBL binding and may prevent viruses from entering host cells; another possibility is that MBL could recognize CMV glycoproteins on the surface of a cell infected with this virus and consequently induce complement-mediated cell destruction [48,49].  

Thus, studies have suggested that deficient MBL concentrations may be a risk factor for symptomatic HHV-2 infection and CMV reactivation; however, it is not yet known how MBL could help control HHV-8 infection and/or the development of KS [50–52]. On the other hand, HHV-8 presents in the viral envelope a mannose carbohydrate structure, glycoprotein B (gB), which could be a potential target for MBL binding [53,54].  

Morais et al (2019), reported that MBL plasma concentration median were significantly lower in the coinfected patient and a possible explanation would be the consumption and reduction of this protein, involving the opsonization of HIV and HHV-8, leading to the reduction of plasma MBL [55]. Because of these results, studies related to MBL plasma concentrations evaluating the HHV-8 latent or latent cycle, quantify of the HHV-8 viral load or measure the activity of MBL in the complement system become essential and may help to understand the role of MBL in the development of KS in HIV/HHV-8 coinfected patients.

Acknowledgments: The Fundação de Amparo à Ciência e Tecnologia de Pernambuco (FACEPE) by the support to Viviane Martha Santos de Morais, according BCT-0187-4.01/18.


  1. S. Mohanna, J.C. Ferrufino, J. Sanchez, F. Bravo, et al. (2005). Epidemiological and clinical characteristics of classic Kaposi’s sarcoma in Peru. J Am Acad Dermatol. 53(3): 435-441.
  2. R.J. Sullivan, L. Pantanowitz, C. Casper, J. Stebbing, et al. (2008).  HIV/AIDS: Epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis. 47(9): 1209-1215.
  3. G.G. de O.M. Cahu, V.M.S. Morais, T.R.R. Lopes, D.M. da Silva, et al. (2016). Prevalence of human herpesvirus 8 infection in people living with HIV/AIDS in Pernambuco, Brazil.  J Med Virol. 88(11): 2016-2020.
  4. M.D. Batista, S. Ferreira, M.M. Sauer, H. Tomiyama,  et al. (2009).  High human herpesvirus 8 (HHV-8) prevalence, clinical correlates and high incidence among recently HIV-1-infected subjects in Sao Paulo, Brazil.  PLoS One. 4(5): 2-6.
  5. F. Broccolo, C.T. Din, M.G. Vigano, T. Rutigliano, (2016).  HHV-8 DNA replication correlates with the clinical status in AIDS-related Kaposi’s sarcoma.  J Clin Virol. 78:47-52.
  6. D.P. Dittmer, B. Damania. (2016).  Kaposi sarcoma - associated herpesvirus : immunobiology , oncogenesis , and therapy. 126(9): 3165-3175.
  7. A.D. Pria, K. Hayward, M. Bower. (2013). Do we still need chemotherapy for AIDS-associated Kaposi’s sarcoma?.  Expert Rev Anticancer Ther. 13(2): 203-209.
  8. D.C. Edelman. (2005).  Human herpesvirus 8--a novel human pathogen. Virol J. 2:78.
  9. M. Auten, A.S. Kim, K.T. Bradley, F.G. Rosado. (2017). Human herpesvirus 8-related diseases: Histopathologic diagnosis and disease mechanisms.  Semin Diagn Pathol. 34(4): 371-376.
  10. P.H. Goncalves, J. Ziegelbauer, T.S. Uldrick, R. Yarchoan. (2017).  Kaposi sarcoma herpesvirus-associated cancers and related diseases. Curr Opin  HIV AIDS. 12(1): 47-56.
  11. D. V Ablashi, L.G. Chatlynne, J.E. Whitman, E. Cesarman. (2002).  Spectrum of Kaposi’s Sarcoma-Associated Herpesvirus , or Human Herpesvirus 8 , Diseases. Clin Microbiol Rev. 15(3): 439-464.
  12. E. Rohner, N. Wyss, S. Trelle, S.M. Mbulaiteye. (2014).  HHV-8 seroprevalence : a global view. Syst Rev. 3:11.
  13. A.D. Pria, K. Hayward, M. Bower. (2013).  Do we still need chemotherapy for AIDS-associated Kaposi’s sarcoma?.  Expert Rev Anticancer Ther. 13(2):  203-209.
  14. Li S, Bai L, Dong J, Sun R , et al.( 2017).  Kaposi’s Sarcoma-Associated Herpesvirus: Epidemiology and Molecular Biology.  Infect Agents Assoc Cancers : Epidemiol & Mol Biol.   P: 91-127.  
  15. C. Areste, D.J. Blackbourn. (2009).  Modulation of the immune system by Kaposi’s sarcoma-associated  herpesvirus.  Trends Microbiol. 17(3) :119-129.
  16. H.R. Lee, K. Brulois, L.Y. Wong, J.U. Jung. (2012).  Modulation of immune system by Kaposi’s sarcoma-associated herpesvirus: Lessons from viral evasion strategies.  Front. Microbiol.  3:44.
  17. K. Brulois, J.U. Jung. (2014).  Interplay between Kaposi’s sarcoma-associated herpesvirus and the innate immune system.  Cytokine Growth Factor Rev. 25(5): 597-609.
  18. J.P. Goncales,  J.V.J. Silva Junior, T.R.R. Lopes, T.R. Tozetto-Mendoza,  et al. (2019).  Association of polymorphisms in NFκB1 promoter and NFκBIA gene with the development of antibodies against HHV-8 in HIV-infected individuals.  Virology.  535: 255-260.
  19. T. Fujita. (2002).   Evolution of the lectin-complement  pathway and its role in innate immunity. Nat Rev Immunol. 2(5): 346-353.
  20. O. Manuel,  M. Pascual,  M. Trendelenburg,  P.R. Meylan. (2007) .  Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation. 83(3) : 359-362.
  21. C.P. Mason, A.W. Tarr. (2015).  Human lectins and their roles in viral infections.  Molecules. 20(2) : 2229-2271.
  22. A.C. Vallinoto,  N.A. Muto,  A.E. Alves,  L.F. Machado, et al. (2008).  Characterization of polymorphisms in the mannose-binding lectin gene promoter among human immunodeficiency virus 1 infected subjects.  Mem Inst Oswaldo Cruz. 103(7) : 645-649.
  23. R.B.L. Zinyama-Gutsire,  C. Chasela,  P. Kallestrup,  S. Rusakaniko,  et al. (2015).  HIV-1 Disease Progression and Survival in an Adult Population in Zimbabwe: Is There an Effect of the Mannose Binding Lectin Deficiency?. Omics : A J Integr Biol. 19(9): 542-552.
  24. M. Martin,  A.M. Blom. (2016).  Complement in removal of the dead - balancing inflammation. Immunol. Rev. 274(1): 218-232.
  25. C. Auriti,  G. Prencipe,  M. Moriondo,  I. Bersani, et al . (2017).  Mannose-Binding Lectin: Biologic Characteristics and Role in the Susceptibility to Infections and Ischemia-Reperfusion Related Injury in Critically Ill Neonates.  J Immunol Res. 2017.
  26. D.L. Worthley,  P.G. Bardy, C.G. Mullighan. (2005).   Mannose-binding lectin: biology and clinical implications.  Intern  Med  J.  35(9): 548-555.
  27. W.K. Eddie, L.M. Stuart,  K. Takahashi, R.A. Ezekowitz, et al. (2009).  Mannose-binding  lectin and innate immunity.  Immunol Rev. 230(1) : 9-21.
  28. J. Dobo, G. Pal,  L. Cervenak,  P. Gal. (2016).  The emerging roles of mannose-binding lectin-associated serine proteases (MASPs) in the lectin pathway of complement and beyond.   Immunol  Rev. 274(1): 98-111.
  29. D.P. Eisen,  R.M. Minchinton. (2003).  Impact of mannose-binding lectin  on susceptibility to infectious diseases.  Clin Infect Dis. 37(11): 1496-1505.
  30. W.K. Ip, K. Takahashi, R.A. Ezekowitz, L.M. Stuart. (2009).  Mannose-binding  lectin and innate immunity.  Immunol  Rev. 230(1): 9-21.
  31. A. Hartz, J. Pagel, A. Humberg, M. Preuss, et al. (2017) .  The association of mannose-binding lectin 2 polymorphisms with outcome in very low birth weight infants.  PLoS One. 12(5): e0178032.
  32. C. Bautista-Rodriguez,  C. Launes,  I. Jordan,  M. Andres, et al . (2017).  Mannose-binding lectin-deficient genotypes as a risk factor of pneumococcal meningitis in infants.  PLoS One 12(5): e0178377.
  33. V.M.S. De Morais,  E.L.S. De Lima,  G.G.D.O.M. Cahu, T.R.R. Lopes, et al. (2018).  MBL2 gene polymorphisms in HHV-8 infection in people living with HIV/AIDS. Retrovirology.  15: 75.
  34. V. Guimaraes,  R. Guimaraes,  L. Brandao,  M.F.P.T. Baldez da Silva, et al. (2008).  Association between MBL2 gene functional polymorphisms and high-risk human papillomavirus infection in Brazilian women.  Hum Immunol.  69(4-5):  273-278.
  35. M. Seppanen,  M.L. Lokki,  M. Lappalainen,  E. Hiltunen-Back, et al. (2009).  Mannose-binding lectin 2 gene polymorphism in recurrent herpes simplex virus 2 infection.   Hum Immunol. 70(4):  218-221.
  36. G. Erdemir,  T.B. Ozkan,  T. Ozgur,  F. Budak, et al. (2015).   Mannose-binding lectin gene polymorphism and chronic hepatitis B infection in children.  Saudi J Gastroenterol.  21(2): 84-9.
  37. H. Xu,  M. Zhao,  T. Wan,  G. Song, et al. (2013).  Association between Mannose-Binding Lectin Gene Polymorphisms and Hepatitis B Virus Infection: A Meta-Analysis.  PLoS One. 8(10): e75371.
  38. G.G. Figueiredo,  R.D. Cezar,  N.M. Freire,  V.G. Teixeira,  et al. (2016).  Mannose-binding lectin gene (MBL2) polymorphisms  related to the mannose-binding lectin low levels are associated to dengue disease severity.   Hum Immunol. 77(7): 571-575.
  39. M. Hundt,  H. Heiken,  R.E. Schmidt. (2000).   Low Mannose-Binding Lectin Serum Concentrations in HIV Long-Term Nonprogressors?.  AIDS Res Hum Retroviruses.  16(17): 1927.
  40. Y. Tan,  L. Liu,  P. Luo,  A. Wang, et al. (2009).  Association between mannose-binding lectin and HIV infection and progression in a Chinese population.  Mol Immunol. 47(2-3):632-638.
  41. A. Egli,  J. Schafer,  M. Osthoff,  S. Thiel, et al. (2013).  Low Levels of Mannan-Binding  Lectin or Ficolins Are Not Associated with an Increased Risk of Cytomegalovirus Disease in HIV-Infected Patients.  PLoS One. 8(1): e51983.
  42. C. Teodorof,  S. Divakar,  B. Soontornniyomkij,  C.L. Achim,  et al. (2014).   Intracellular mannose binding lectin  mediates  subcellular  trafficking of HIV-1 gp120 in neurons.  Neurobiol Dis.  69: 54-64.
  43. G. Catano, B.K. Agan, H. Kulkarni, V. Telles, et al. (2008).  Independent effects of genetic variations in mannose-binding lectin influence the course of HIV disease: the advantage of heterozygosity for coding mutations.  J Infect Dis. 198(1): 72-80.
  44. N.M. Thielens,  P. Tacnet-Delorme,  G.J. Arlaud. (2002).   Interaction of C1q and mannan-binding lectin with viruses.  Immunobiology.  205(4-5): 563-574.
  45. W.K.E. Ip,  K.H. Chan,  H.K.W. Law,  G.H.W. Tso, et al. (2005).  Mannose‐Binding Lectin in Severe Acute Respiratory Syndrome Coronavirus Infection.  J Infect Dis. 191(10): 1697-1704.
  46. K.A. Stoermer, T.E. Morrison. (2011).  Complement and viral pathogenesis.  Virology.  411(2): 362-373.
  47. M. Brudner,  M. Karpel,  C. Lear,  L. Chen, et al. (2013).  Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane  C-type Lectin Receptors.   PLoS One. 8(4):e60838.
  48. C. Cervera,  F. Lozano,  N. Saval,  I. Gimferrer,  A. Ibanez, et al. (2007).  The Influence of Innate Immunity Gene Receptors Polymorphisms in Renal Transplant Infections.  Transplantation.  83(11): 1493-1500.
  49. W. Wu,  Y. Chen,  H. Qiao,  R. Tao, et al. (2012) .  Human mannose-binding lectin inhibits human cytomegalovirus  infection in human embryonic pulmonary fibroblast.  Apmis. 120(8): 675-682.
  50. M. Gadjeva,  S.R. Paludan,  S. Thiel,  V. Slavov, et al. (2004).  Mannan-binding  lectin modulates the response to HSV-2 infection.  Clin Exp Immunol. 138(2): 304-311.
  51. O. Manuel,  M. Pascual,  M. Trendelenburg,  P.R. Meylan. (2007).  Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation., Transplantation. 83(3): 359-362.
  52. J.M. Kwakkel-van Erp,  A.W.M. Paantjens,  D.A. van Kessel,  J.C. Grutters, et al. (2011).    Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation.  Clin  Exp Immunol. 165(3): 410-416.
  53.  S. Chakraborty,  M.V. Veettil,  B. Chandran. (2012).   Kaposi’s sarcoma associated herpesvirus entry into target cells.  Front. Microbiol.  3:6.
  54. H.R. Hensler,  M.J. Tomaszewski,  G. Rappocciolo,  C.R. Rinaldo, et al. (2014).   Human herpesvirus 8 glycoprotein B binds the entry receptor DC-SIGN. Virus Res. 190: 97-103.
  55.  V.M.S. De Morais, J.P. Goncales, G.G.D.O.M. Cahu, T.R. Tozetto-Mendoza, et al. (2019).   Mannose-binding lectin concentrations in people living with HIV/AIDS infected by HHV-8.  BMC Immunol. 20(1):1.


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