Protection from primary human immunodeficiency virus type 1 (HIV-1) infection has not yet been accomplished by vaccines inducing HIV-1-specific acquired immunity. Nevertheless, it has been reported that a small subgroup of women remain resistant to HIV-1 infection under natural conditions. If similar conditions can be induced in uninfected individuals, it will contribute the first line of protection against HIV-1 infection, and also improve the effects of anti-HIV-1 vaccines. We reasoned that innate immunity may be involved in the resistance to HIV-1 infection, and investigated the effects of various Toll-like receptor (TLR) ligands and commensal bacteria on HIV-1 replication in macrophages, one of the initial targets of HIV-1 infection and also the main mediators of innate immunity. We established the HIV-1 reporter monocytic cell line, THP-1/NL4-3luc, which could be differentiated into macrophage-like cells . In these cells, stimulation of TLR3 and TLR4 by their ligands suppressed HIV-1 expression partly through type I interferon (IFN). Among the commensal bacteria tested, , and suppressed HIV-1 expression, whereas , , and enhanced it. The bacteria with suppressive effects preferentially stimulated TLR4, whereas the ones with enhancing effects stimulated TLR2. Neutralizing antibodies against TLR4 and IFN-/ receptor abrogated bacterially mediated HIV-1 suppression. Suppressive effects of , and on HIV-1 replication were reproducible in primary monocyte-derived macrophages following acute HIV-1 infection. These findings suggest that certain commensal bacteria preferentially stimulating TLR4 potentially produce local environments resistant to HIV-1 infection.


Article metrics loading...

Loading full text...

Full text loading...



  1. Auwerx, J.(1991). The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation. Experientia 47, 22–31.[CrossRef] [Google Scholar]
  2. Barouch, D. H.(2008). Challenges in the development of an HIV-1 vaccine. Nature 455, 613–619.[CrossRef] [Google Scholar]
  3. Beignon, A. S., McKenna, K., Skoberne, M., Manches, O., DaSilva, I., Kavanagh, D. G., Larsson, M., Gorelick, R. J., Lifson, J. D. & Bhardwaj, N.(2005). Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor–viral RNA interactions. J Clin Invest 115, 3265–3275.[CrossRef] [Google Scholar]
  4. Biasin, M., Piacentini, L., Lo Caputo, S., Naddeo, V., Pierotti, P., Borelli, M., Trabattoni, D., Mazzotta, F., Shearer, G. M. & Clerici, M.(2010). TLR activation pathways in HIV-1-exposed seronegative individuals. J Immunol 184, 2710–2717.[CrossRef] [Google Scholar]
  5. Bouskra, D., Brezillon, C., Berard, M., Werts, C., Varona, R., Boneca, I. G. & Eberl, G.(2008). Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510.[CrossRef] [Google Scholar]
  6. Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C. & Lusso, P.(1995). Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815.[CrossRef] [Google Scholar]
  7. Doyle, S., Vaidya, S., O'Connell, R., Dadgostar, H., Dempsey, P., Wu, T., Rao, G., Sun, R., Haberland, M. & other authors(2002). IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17, 251–263.[CrossRef] [Google Scholar]
  8. Equils, O., Schito, M. L., Karahashi, H., Madak, Z., Yarali, A., Michelsen, K. S., Sher, A. & Arditi, M.(2003). Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: implications of simultaneous activation of TLRs on HIV replication. J Immunol 170, 5159–5164.[CrossRef] [Google Scholar]
  9. Equils, O., Salehi, K. K., Cornataeanu, R., Lu, D., Singh, S., Whittaker, K. & Baldwin, G. C.(2006). Repeated lipopolysaccharide (LPS) exposure inhibits HIV replication in primary human macrophages. Microbes Infect 8, 2469–2476.[CrossRef] [Google Scholar]
  10. Fowke, K. R., Nagelkerke, N. J., Kimani, J., Simonsen, J. N., Anzala, A. O., Bwayo, J. J., MacDonald, K. S., Ngugi, E. N. & Plummer, F. A.(1996). Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet 348, 1347–1351.[CrossRef] [Google Scholar]
  11. Gurney, K. B., Colantonio, A. D., Blom, B., Spits, H. & Uittenbogaart, C. H.(2004). Endogenous IFN-α production by plasmacytoid dendritic cells exerts an antiviral effect on thymic HIV-1 infection. J Immunol 173, 7269–7276.[CrossRef] [Google Scholar]
  12. Heggelund, L., Muller, F., Lien, E., Yndestad, A., Ueland, T., Kristiansen, K. I., Espevik, T., Aukrust, P. & Froland, S. S.(2004). Increased expression of Toll-like receptor 2 on monocytes in HIV infection: possible roles in inflammation and viral replication. Clin Infect Dis 39, 264–269.[CrossRef] [Google Scholar]
  13. Herbeuval, J. P. & Shearer, G. M.(2007). HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 123, 121–128.[CrossRef] [Google Scholar]
  14. Hijiya, N., Miyake, K., Akashi, S., Matsuura, K., Higuchi, Y. & Yamamoto, S.(2002). Possible involvement of Toll-like receptor 4 in endothelial cell activation of larger vessels in response to lipopolysaccharide. Pathobiology 70, 18–25.[CrossRef] [Google Scholar]
  15. Hirai, H., Suzuki, T., Fujisawa, J., Inoue, J. & Yoshida, M.(1994). Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor κB and induces nuclear translocation of transcription factor NF-κB proteins for transcriptional activation. Proc Natl Acad Sci U S A 91, 3584–3588.[CrossRef] [Google Scholar]
  16. Hosmalin, A. & Lebon, P.(2006). Type I interferon production in HIV-infected patients. J Leukoc Biol 80, 984–993.[CrossRef] [Google Scholar]
  17. Ikeda, T., Nishitsuji, H., Zhou, X., Nara, N., Ohashi, T., Kannagi, M. & Masuda, T.(2004). Evaluation of the functional involvement of human immunodeficiency virus type 1 integrase in nuclear import of viral cDNA during acute infection. J Virol 78, 11563–11573.[CrossRef] [Google Scholar]
  18. Johnson-Henry, K. C., Donato, K. A., Shen-Tu, G., Gordanpour, M. & Sherman, P. M.(2008).Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157 : H7-induced changes in epithelial barrier function. Infect Immun 76, 1340–1348.[CrossRef] [Google Scholar]
  19. Kaul, R., Trabattoni, D., Bwayo, J. J., Arienti, D., Zagliani, A., Mwangi, F. M., Kariuki, C., Ngugi, E. N., MacDonald, K. S. & other authors(1999). HIV-1-specific mucosal IgA in a cohort of HIV-1-resistant Kenyan sex workers. AIDS 13, 23–29.[CrossRef] [Google Scholar]
  20. Kaul, R., Plummer, F. A., Kimani, J., Dong, T., Kiama, P., Rostron, T., Njagi, E., MacDonald, K. S., Bwayo, J. J. & other authors(2000). HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi. J Immunol 164, 1602–1611.[CrossRef] [Google Scholar]
  21. Kaul, R., Rowland-Jones, S. L., Kimani, J., Dong, T., Yang, H. B., Kiama, P., Rostron, T., Njagi, E., Bwayo, J. J. & other authors(2001). Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses. J Clin Invest 107, 341–349.[CrossRef] [Google Scholar]
  22. Klebanoff, S. J. & Coombs, R. W.(1991). Viricidal effect of Lactobacillus acidophilus on human immunodeficiency virus type 1: possible role in heterosexual transmission. J Exp Med 174, 289–292.[CrossRef] [Google Scholar]
  23. Koyanagi, Y., Miles, S., Mitsuyasu, R. T., Merrill, J. E., Vinters, H. V. & Chen, I. S.(1987). Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science 236, 819–822.[CrossRef] [Google Scholar]
  24. Liu, X., Mosoian, A., Li-Yun Chang, T., Zerhouni-Layachi, B., Snyder, A., Jarvis, G. A. & Klotman, M. E.(2006). Gonococcal lipooligosaccharide suppresses HIV infection in human primary macrophages through induction of innate immunity. J Infect Dis 194, 751–759.[CrossRef] [Google Scholar]
  25. Mares, D., Simoes, J. A., Novak, R. M. & Spear, G. T.(2008). TLR2-mediated cell stimulation in bacterial vaginosis. J Reprod Immunol 77, 91–99.[CrossRef] [Google Scholar]
  26. Matera, G., Muto, V., Vinci, M., Zicca, E., Abdollahi-Roodsaz, S., van de Veerdonk, F. L., Kullberg, B. J., Liberto, M. C., van der Meer, J. W. & other authors(2009). Receptor recognition of and immune intracellular pathways for Veillonella parvula lipopolysaccharide. Clin Vaccine Immunol 16, 1804–1809.[CrossRef] [Google Scholar]
  27. Meier, A., Alter, G., Frahm, N., Sidhu, H., Li, B., Bagchi, A., Teigen, N., Streeck, H., Stellbrink, H. J. & other authors(2007). MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81, 8180–8191.[CrossRef] [Google Scholar]
  28. Meltzer, M. S., Nakamura, M., Hansen, B. D., Turpin, J. A., Kalter, D. C. & Gendelman, H. E.(1990). Macrophages as susceptible targets for HIV infection, persistent viral reservoirs in tissue, and key immunoregulatory cells that control levels of virus replication and extent of disease. AIDS Res Hum Retroviruses 6, 967–971. [Google Scholar]
  29. NCCLS(1992). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard M27-A2, 2nd edn. Wayne, PA: Clinical and Laboratory Standards Institute. http://www.clsi.org/source/orders/free/M27-A3.pdf.
  30. Ogawa, Y., Kawamura, T., Kimura, T., Ito, M., Blauvelt, A. & Shimada, S.(2009). Gram-positive bacteria enhance HIV-1 susceptibility in Langerhans cells, but not in dendritic cells, via Toll-like receptor activation. Blood 113, 5157–5166.[CrossRef] [Google Scholar]
  31. Planelles, V., Haislip, A., Withers-Ward, E. S., Stewart, S. A., Xie, Y., Shah, N. P. & Chen, I. S.(1995). A new reporter system for detection of retroviral infection. Gene Ther 2, 369–376. [Google Scholar]
  32. Plummer, F. A., Ball, T. B., Kimani, J. & Fowke, K. R.(1999). Resistance to HIV-1 infection among highly exposed sex workers in Nairobi: what mediates protection and why does it develop? Immunol Lett 66, 27–34.[CrossRef] [Google Scholar]
  33. Ravanfar, P., Mendoza, N., Satyaprakash, A. & Jordan, B. I.(2009). HIV vaccines under study. Dermatol Ther 22, 158–167.[CrossRef] [Google Scholar]
  34. Resta-Lenert, S. & Barrett, K. E.(2006). Probiotics and commensals reverse TNF-α- and IFN-γ-induced dysfunction in human intestinal epithelial cells. Gastroenterology 130, 731–746.[CrossRef] [Google Scholar]
  35. Romano Carratelli, C., Mazzola, N., Paolillo, R., Sorrentino, S. & Rizzo, A.(2009). Toll-like receptor-4 (TLR4) mediates human β-defensin-2 (HBD-2) induction in response to Chlamydia pneumoniae in mononuclear cells. FEMS Immunol Med Microbiol 57, 116–124.[CrossRef] [Google Scholar]
  36. Sekaly, R. P.(2008). The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J Exp Med 205, 7–12.[CrossRef] [Google Scholar]
  37. Shattock, R. J., Friedland, J. S. & Griffin, G. E.(1993). Release of human immunodeficiency virus by THP-1 cells and human macrophages is regulated by cellular adherence and activation. J Virol 67, 3569–3575. [Google Scholar]
  38. Simard, S., Maurais, E., Gilbert, C. & Tremblay, M. J.(2008). LPS reduces HIV-1 replication in primary human macrophages partly through an endogenous production of type I interferons. Clin Immunol 127, 198–205.[CrossRef] [Google Scholar]
  39. Spear, G. T., St John, E. & Zariffard, M. R.(2007). Bacterial vaginosis and human immunodeficiency virus infection. AIDS Res Ther 4, 25.[CrossRef] [Google Scholar]
  40. Takeda, K. & Akira, S.(2004). TLR signaling pathways. Semin Immunol 16, 3–9.[CrossRef] [Google Scholar]
  41. Trapp, S., Derby, N. R., Singer, R., Shaw, A., Williams, V. G., Turville, S. G., Bess, J. W., Jr, Lifson, J. D. & Robbiani, M.(2009). Double-stranded RNA analog poly(I : C) inhibits human immunodeficiency virus amplification in dendritic cells via type I interferon-mediated activation of APOBEC3G. J Virol 83, 884–895.[CrossRef] [Google Scholar]
  42. Troy, E. B. & Kasper, D. L.(2010). Beneficial effects of Bacteroides fragilis polysaccharides on the immune system. Front Biosci 15, 25–34.[CrossRef] [Google Scholar]
  43. Verani, A., Scarlatti, G., Comar, M., Tresoldi, E., Polo, S., Giacca, M., Lusso, P., Siccardi, A. G. & Vercelli, D.(1997). C–C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells. J Exp Med 185, 805–816.[CrossRef] [Google Scholar]
  44. Zarember, K. A. & Godowski, P. J.(2002). Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168, 554–561.[CrossRef] [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error