Harnessing innate immune responses to enhance anti-HIV-1 therapies

Main Article Content

Alexandra L Howell


Innate immune responses represent the first line of defense against invading microbes including HIV-1. Macrophages and other myeloid cell populations mediate responses to viruses, bacteria and fungi in a rapid, non-specific manner following binding of moieties from these pathogens to innate immune receptors. Macrophages express several types of innate immune receptors called “pattern recognition receptors” that bind distinct pathogen-associated molecular patterns. Chief among the innate immune receptors in macrophages are a family of receptors called the Toll-like receptors that reside on the plasma membrane as well as within endosomal vesicles. The binding of ligand to Toll-like receptors and other types of innate immune receptors triggers a down-stream signaling cascade designed to rapidly induce expression of inflammatory mediators and innate immune molecules to thwart infection. Several nucleic acid based approaches have been developed to block or eliminate HIV-1 infection of macrophages and other myeloid cells, including the use of short-interfering RNA to block viral and cellular protein expression, and more recently, genomic engineering with CRISPR/Cas to cleave viral or cellular genes important in HIV-1 infection and replication. However, because these constructs are comprised of nucleic acids, they function as powerful ligands to activate select innate immune receptors, triggering anti-viral responses that effectively inhibit HIV-1 infection. This review will summarize the potential dual-benefits of nucleic acid-based therapies to block HIV-1 infection of macrophages.

Article Details

How to Cite
HOWELL, Alexandra L. Harnessing innate immune responses to enhance anti-HIV-1 therapies. Medical Research Archives, [S.l.], n. 3, july 2015. ISSN 2375-1924. Available at: <http://journals.ke-i.org/index.php/mra/article/view/285>. Date accessed: 17 oct. 2017.
Innate Immunity, Macrophages, HIV-1, inflammation, Toll-like receptors
Review Articles


Akira, S., S. Uematsu and O. Takeuchi (2006). "Pathogen recognition and innate immunity." Cell 124(4): 783-801.

Ayinde, D., N. Casartelli and O. Schwartz (2012). "Restricting HIV the SAMHD1 way: through nucleotide starvation." Nat Rev Microbiol 10(10): 675-680.

Banerjee, A., R. Benjamin, K. Balakrishnan, P. Ghosh and S. Banerjee (2014). "Human protein Staufen-2 promotes HIV-1 proliferation by positively regulating RNA export activity of viral protein Rev." Retrovirology 11: 18.

Berkhout, B. and O. ter Brake (2009). "Towards a durable RNAi gene therapy for HIV-AIDS." Expert Opin Biol Ther 9(2): 161-170.

Bi, Y., L. Sun, D. Gao, C. Ding, Z. Li, Y. Li, W. Cun and Q. Li (2014). "High-efficiency targeted editing of large viral genomes by RNA-guided nucleases." PLoS Pathog 10(5): e1004090.

Bishop, K. N., M. Verma, E. Y. Kim, S. M. Wolinsky and M. H. Malim (2008). "APOBEC3G inhibits elongation of HIV-1 reverse transcripts." PLoS Pathog 4(12): e1000231.

Buitendijk, M., S. K. Eszterhas and A. L. Howell (2013). "Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells." AIDS Res Hum Retroviruses 29(6): 907-918.

Buitendijk, M., S. K. Eszterhas and A. L. Howell (2014). "Toll-like receptor agonists are potent inhibitors of human immunodeficiency virus-type 1 replication in peripheral blood mononuclear cells." AIDS Res Hum Retroviruses 30(5): 457-467.

Burugu, S., A. Daher, E. F. Meurs and A. Gatignol (2014). "HIV-1 translation and its regulation by cellular factors PKR and PACT." Virus Res 193: 65-77.

Caramalho, I., T. Lopes-Carvalho, D. Ostler, S. Zelenay, M. Haury and J. Demengeot (2003). "Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide." J Exp Med 197(4): 403-411.

Carias, A. M., S. McCoombe, M. McRaven, M. Anderson, N. Galloway, N. Vandergrift, A. J. Fought, J. Lurain, M. Duplantis, R. S. Veazey and T. J. Hope (2013). "Defining the interaction of HIV-1 with the mucosal barriers of the female reproductive tract." J Virol 87(21): 11388-11400.

Chakrabarti, A., B. K. Jha and R. H. Silverman (2011). "New insights into the role of RNase L in innate immunity." J Interferon Cytokine Res 31(1): 49-57.

Cros, J., N. Cagnard, K. Woollard, N. Patey, S. Y. Zhang, B. Senechal, A. Puel, S. K. Biswas, D. Moshous, C. Picard, J. P. Jais, D. D'Cruz, J. L. Casanova, C. Trouillet and F. Geissmann (2010). "Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors." Immunity 33(3): 375-386.

de Fougerolles, A., H. P. Vornlocher, J. Maraganore and J. Lieberman (2007). "Interfering with disease: a progress report on siRNA-based therapeutics." Nat Rev Drug Discov 6(6): 443-453.

Deeken, J. F., L. Pantanowitz and B. J. Dezube (2009). "Targeted therapies to treat non-AIDS-defining cancers in patients with HIV on HAART therapy: treatment considerations and research outlook." Curr Opin Oncol 21(5): 445-454.

Douagi, I., C. Gujer, C. Sundling, W. C. Adams, A. Smed-Sorensen, R. A. Seder, G. B. Karlsson Hedestam and K. Lore (2009). "Human B cell responses to TLR ligands are differentially modulated by myeloid and plasmacytoid dendritic cells." J Immunol 182(4): 1991-2001.

Drake, M. J. and P. Bates (2015). "Application of gene-editing technologies to HIV-1." Curr Opin HIV AIDS 10(2): 123-127.

Engelmann, I., F. Dubos, P. E. Lobert, C. Houssin, V. Degas, A. Sardet, A. Decoster, A. Dewilde, A. Martinot and D. Hober (2015). "Diagnosis of viral infections using myxovirus resistance protein A (MxA)." Pediatrics 135(4): e985-993.

Eszterhas, S. K., N. O. Ilonzo, J. E. Crozier, S. Celaj and A. L. Howell (2011). "Nanoparticles containing siRNA to silence CD4 and CCR5 reduce expression of these receptors and inhibit HIV-1 infection in human female reproductive tract tissue explants." Infect Dis Rep 3(2): e11.

Feng, Z., G. R. Dubyak, M. M. Lederman and A. Weinberg (2006). "Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4." J Immunol 177(2): 782-786.

Franchin, G., G. Zybarth, W. W. Dai, L. Dubrovsky, N. Reiling, H. Schmidtmayerova, M. Bukrinsky and B. Sherry (2000). "Lipopolysaccharide inhibits HIV-1 infection of monocyte- derived macrophages through direct and sustained down-regulation of CC chemokine receptor 5." J Immunol 164(5): 2592-2601.

Franke, E. K. and J. Luban (1995). "Cyclophilin and gag in HIV-1 replication and pathogenesis." Adv Exp Med Biol 374: 217-228.

Giraldo, D. M., J. C. Hernandez and S. U. Inchima (2015). "Impact of in vitro costimulation with TLR2, TLR4 and TLR9 agonists and HIV-1 on antigen-presenting cell activation." Intervirology 58(2): 122-129.

Hancks, D. C., M. K. Hartley, C. Hagan, N. L. Clark and N. C. Elde (2015). "Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape." PLoS Genet 11(5): e1005203.

Harris, R. S., K. N. Bishop, A. M. Sheehy, H. M. Craig, S. K. Petersen-Mahrt, I. N. Watt, M. S. Neuberger and M. H. Malim (2003). "DNA deamination mediates innate immunity to retroviral infection." Cell 113(6): 803-809.

Hornung, V., M. Guenthner-Biller, C. Bourquin, A. Ablasser, M. Schlee, S. Uematsu, A. Noronha, M. Manoharan, S. Akira, A. de Fougerolles, S. Endres and G. Hartmann (2005). "Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7." Nat Med 11(3): 263-270.

Jha, B. K., I. Polyakova, P. Kessler, B. Dong, B. Dickerman, G. C. Sen and R. H. Silverman (2011). "Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity." J Biol Chem 286(30): 26319-26326.

Jia, X., Q. Zhao and Y. Xiong (2015). "HIV suppression by host restriction factors and viral immune evasion." Curr Opin Struct Biol 31: 106-114.

Judge, A. D., V. Sood, J. R. Shaw, D. Fang, K. McClintock and I. MacLachlan (2005). "Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA." Nat Biotechnol 23(4): 457-462.

Kawai, T. and S. Akira (2006). "Innate immune recognition of viral infection." Nat Immunol 7(2): 131-137.

Khalili, K., R. Kaminski, J. Gordon, L. Cosentino and W. Hu (2015). "Genome editing strategies: potential tools for eradicating HIV-1/AIDS." J Neurovirol 21(3): 310-321.

Lohofener, J., N. Steinke, P. Kay-Fedorov, P. Baruch, A. Nikulin, S. Tishchenko, D. J. Manstein and R. Fedorov (2015). "The Activation Mechanism of 2'-5'-Oligoadenylate Synthetase Gives New Insights Into OAS/cGAS Triggers of Innate Immunity." Structure 23(5): 851-862.

Maggio, I., M. Holkers, J. Liu, J. M. Janssen, X. Chen and M. A. Goncalves (2014). "Adenoviral vector delivery of RNA-guided CRISPR/Cas9 nuclease complexes induces targeted mutagenesis in a diverse array of human cells." Sci Rep 4: 5105.

Mehlotra, R. K., P. A. Zimmerman, A. Weinberg and R. J. Jurevic (2013). "Variation in human beta-defensin genes: new insights from a multi-population study." Int J Immunogenet 40(4): 261-269.

Munir, M. and M. Berg (2013). "The multiple faces of proteinkinase R in antiviral defense." Virulence 4(1): 85-89.

Nasu, K. and H. Narahara (2010). "Pattern recognition via the toll-like receptor system in the human female genital tract." Mediators Inflamm 2010: 976024.

Olivetta, E., V. Tirelli, C. Chiozzini, B. Scazzocchio, I. Romano, C. Arenaccio and M. Sanchez (2014). "HIV-1 Nef impairs key functional activities in human macrophages through CD36 downregulation." PLoS One 9(4): e93699.

Robbins, M., A. Judge, E. Ambegia, C. Choi, E. Yaworski, L. Palmer, K. McClintock and I. MacLachlan (2008). "Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation." Hum Gene Ther 19(10): 991-999.

Royce, R. A., A. Sena, W. Cates, Jr. and M. S. Cohen (1997). "Sexual transmission of HIV." N Engl J Med 336(15): 1072-1078.

Sagar, M. (2014). "Origin of the transmitted virus in HIV infection: infected cells versus cell-free virus." J Infect Dis 210 Suppl 3: S667-673.

Sayah, D. M., E. Sokolskaja, L. Berthoux and J. Luban (2004). "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1." Nature 430(6999): 569-573.

Sheehy, A. M., N. C. Gaddis, J. D. Choi and M. H. Malim (2002). "Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein." Nature 418(6898): 646-650.

Shen, R., H. E. Richter and P. D. Smith (2014). "Interactions between HIV-1 and mucosal cells in the female reproductive tract." Am J Reprod Immunol 71(6): 608-617.

Sokolskaja, E. and J. Luban (2006). "Cyclophilin, TRIM5, and innate immunity to HIV-1." Curr Opin Microbiol 9(4): 404-408.

Song, Y., Y. Zhuang, S. Zhai, D. Huang, Y. Zhang, W. Kang, X. Li, Q. Liu, Q. Yu and Y. Sun (2009). "Increased expression of TLR7 in CD8(+) T cells leads to TLR7-mediated activation and accessory cell-dependent IFN-gamma production in HIV type 1 infection." AIDS Res Hum Retroviruses 25(12): 1287-1295.

Stremlau, M., C. M. Owens, M. J. Perron, M. Kiessling, P. Autissier and J. Sodroski (2004). "The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys." Nature 427(6977): 848-853.

Strong, C. L., H. P. Guerra, K. R. Mathew, N. Roy, L. R. Simpson and M. R. Schiller (2015). "Damaging the Integrated HIV Proviral DNA with TALENs." PLoS One 10(5): e0125652.

Swaminathan, S., H. Sui, J. W. Adelsberger, Q. Chen, M. Sneller, S. A. Migueles, S. Kottilil, A. Ober, S. Jones, C. A. Rehm, H. C. Lane and T. Imamichi (2014). "HIV-1 Treated Patients with Undetectable Viral Loads have Lower Levels of Innate Immune Responses via Cytosolic DNA Sensing Systems Compared with Healthy Uninfected Controls." J AIDS Clin Res 5(6).

Victoria, S., J. R. Temerozo, L. Gobbo, H. K. Pimenta-Inada and D. C. Bou-Habib (2013). "Activation of Toll-like receptor 2 increases macrophage resistance to HIV-1 infection." Immunobiology 218(12): 1529-1536.

Wang, W., C. Ye, J. Liu, D. Zhang, J. T. Kimata and P. Zhou (2014). "CCR5 gene disruption via lentiviral vectors expressing Cas9 and single guided RNA renders cells resistant to HIV-1 infection." PLoS One 9(12): e115987.

Wayengera, M. (2011). "Proviral HIV-genome-wide and pol-gene specific zinc finger nucleases: usability for targeted HIV gene therapy." Theor Biol Med Model 8: 26.

Westhorpe, C. L., J. Zhou, N. L. Webster, B. Kalionis, S. R. Lewin, A. Jaworowski, W. A. Muller and S. M. Crowe (2009). "Effects of HIV-1 infection in vitro on transendothelial migration by monocytes and monocyte-derived macrophages." J Leukoc Biol 85(6): 1027-1035.

Wheeler, L. A. (2014). "Silencing sexually transmitted infections: topical siRNA-based interventions for the prevention of HIV and HSV." Infect Dis Obstet Gynecol 2014: 125087.

Yoh, S. M., M. Schneider, J. Seifried, S. Soonthornvacharin, R. E. Akleh, K. C. Olivieri, P. D. De Jesus, C. Ruan, E. de Castro, P. A. Ruiz, D. Germanaud, V. des Portes, A. Garcia-Sastre, R. Konig and S. K. Chanda (2015). "PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1." Cell 161(6): 1293-1305.

Zhou, Y., X. Wang, M. Liu, Q. Hu, L. Song, L. Ye, D. Zhou and W. Ho (2010). "A critical function of toll-like receptor-3 in the induction of anti-human immunodeficiency virus activities in macrophages." Immunology 131(1): 40-49.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.