How Intestinal Bacteria Can Promote HIV Replication

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1 AIDS Reviews. Rev. 2013;15: How Intestinal Bacteria Can Promote Replication Zhanjun Shu 1, Jianping Ma 1, Dilinuer Tuerhong 1, Chengxin Yang 2 and Halmurat Upur 3 1 Division of AIDS Research, National Traditional Chinese Medicine Clinical Research Bases in Xinjiang, Urumuqi, China; 2 Infectious Disease Dept. The Sixth People Hospital in Xinjiang Uygur Autonomous Region, China; 3 Xinjiang Medical University, Xinjiang, China Abstract Since the 1950s, researchers have gradually realized that the body s bacteria help fight infection by crowding out potential pathogens. In the past decades, scientists have even begun to see our microbiota as thick and thin allies. However, the influence of gut bacteria on is largely unknown. Our review likely sheds light on the previously indistinct role of commensal microbiota in retroviral pathogenesis. The delicate yet critical balance between this enormous bacterial population and the gastrointestinal tract is gradually destroyed along with incursion. The leakage into the systemic circulation of bacterial and byproducts such as lipopolysaccharide directly stimulates the innate immune system through toll like receptors. As a result, toll like receptor 4 activation provokes production of interleukin 10, which mediates immunological tolerance. Therefore, a solid deduction is that intestinal microbes may be involved in triggering of replication and transmission of, just like other retroviruses. (AIDS Rev. 2013;15:32-7) Corresponding author: Halmurat Upur, shu @163.com Key words Intestinal bacteria. replication. Introduction The adult human intestine lives with an almost inconceivable number of microorganisms. The scale of the population (up to 100 trillion) far exceeds that of all other microbial communities associated with the body s surfaces and is ~10 times greater than the total number of our somatic and germ cells 1, not to mention other viruses and parasitic eukaryotic microbes. Since the 1950s, researchers have recognized that the body s bacteria help fight infection by crowding out potential pathogens. As a result, intestinal bacteria aid host health and limit bacterial pathogen colonization. In the past decades, scientists have even begun to see our microbiota as thick and thin allies. Gut bacteria Correspondence to: Halmurat Upur Xinjiang Medical University Xinyi Road NO.393. Xinjiang Autonomous Region , PR China E mail: shu @163.com help shape the developing immune system; for instance, mice lacking their natural gut bacteria, known as germ free mice, are more susceptible to several viruses. Meanwhile, gut bacteria can store, consume, and redistribute energy, mediate physiologically important chemical transformations, and repair itself through self replication 2. In fact, it is undeniable that intestinal microflora comprises a highly active society of organisms, possessing a diverse complex of enzymes that perform extremely varied functions, both beneficial and detrimental 3. However, the influence of gut bacteria on is largely unknown. In 2011, Kuss, et al. found that poliovirus binds lipopolysaccharide (LPS), and exposure of poliovirus to bacteria enhanced host cell association and infection. At the same time the pathogenesis of reovirus, an unrelated enteric virus, also was more severe in the presence of intestinal microbes. They suggested that intestinal microbiota promote enteric virus replication and systemic pathogenesis 4. Another similar research also showed that a retrovirus covers itself with molecules from natural gut bacteria, and these molecules interact with toll like receptor 4 (TLR 4), a mouse immune system receptor, to make viral infection possible 5.

2 Zhanjun Shu, et al.: How Intestinal Bacteria Can Promote Replication Consequently, retroviruses employ various mechanisms of immune evasion 6,7 and can destroy the immune system (e.g. immunodeficiency viruses of various species) or subvert it 7,8 to enable successful transmission 9. Undoubtedly, it is exciting and inspiring for us to re examine the relationship between intestinal bacteria and viruses. It is urgent to determine what kind of roles gut flora play: protective or abetting roles, or both protective and abetting roles. Intestinal mucosa immune function The primary cellular barrier of the gastrointestinal tract (GIT) in preventing foreign bacteria and antigens encountering the immune system is the single layer of gut epithelium, the surface area of which is expanded to the order of 400 m 2, largely because it is formed into millions of fingerlike villi in the small bowel. Each epithelial cell maintains an intimate association with its neighbors and seals the surface of the gut with tight junctions. In the intestines, the single layer of epithelium separates the body from the outside world. This physical barrier also represents a dynamic interface between the host immune system and the luminal environment, which is loaded with a plethora of foreign antigens and (potentially harmful) microbes 10. In the upper bowel, the bulk of the antigen exposure comes from daily diet, whereas in the ileum and colon, the additional antigenic load of an abundant and highly complex commensal microflora exists 11. The gastrointestinal tract, which is about eight meters long, houses most (40 65% or more) of the body s total immune cells 12. These cells are organized into two types of structures consistent with their role in the mucosal immune system: inductive sites and effector sites. Inductive sites (e.g. Peyer s patches in the small intestine and lymphoid follicles in the colon) are organized aggregates analogous to peripheral lymph nodes. In inductive sites, antigen presenting cells (APC) provide processed antigen to naive lymphocytes within distinct T and B cell zones. Mucosal effector sites are comprised of intraepithelial and lamina propria lymphocytes disseminated throughout most of the GIT. Intraepithelial lymphocytes in humans are primarily CD8 + T cells with a minority (< 10%) of γδ T cells. Throughout the large and small intestine, the single cell columnar epithelium is underlain by a basement membrane, beneath which lies the lamina propria, heavily populated in health with CD4 + T cells and some plasma cells such as macrophages, dendritic cells (DC), mast cells, and eosinophils 11,13. Macrophages and DC are present in both inductive and effector sites 11,14. Meanwhile, microfolded cells, or M cells, are modified epithelial cells that take up and transfer antigen and some pathogens to underlying inductive sites. In the normal GIT environment, M cells can transport antigens from the lumen of the intestine to Peyer s patches, thus allowing the adaptive arm of the immune system to sample enteric antigens 15. Distribution and characteristics of human dendritic cell subsets Dendritic cells, as sentinels of the immune system, are strategically located in skin, mucosal tissues, and blood to monitor acquisition of infection. Through expression of a diverse array of receptors and signaling molecules, DC capture pathogens and trigger innate and adaptive immune responses. They are professional antigen presenting cells, and produce cytokines that mediate direct effector and immunoregulatory functions. In humans, there are two major dendritic cell subsets, conventional CD11c + myeloid dendritic cells (cdc) and plasmacytoid dendritic cells (pdc, which are CD11c 10 ). Located in skin (as Langerhans cells and dermal dendritic cells), genital/gut mucosa and in blood, cdc are poised to encounter 1 in the initial stages of infection. Plasmacytoid DC are found in blood, thymus, inflamed skin, and mucosa and lymph nodes, and may first encounter during early local viral replication/spread. Both cdc and pdc serve as critical links between innate and adaptive immune responses through expression of pattern recognition receptors (PRR), such as toll like receptors (TLR) and C type lectins, and intracellular pathogen sensors, which trigger specific signaling pathways that lead to host defense 16. This low grade inflammatory state likely reflects ongoing contact with intestinal flora, and appears to be tightly regulated to maintain mucosal integrity and clinical health. Pattern recognition receptors and toll like receptors Cells of the innate immune system utilize PRR to identify viral pathogens by engaging pathogen associated molecular patterns. During viral infections, the innate immune system uses PRR to trigger a rapid defense program to eliminate viruses and, at the same 33

3 AIDS Reviews. 2013;15 34 time, direct appropriate adaptive immune responses. Two different classes of PRR are involved, TLR and the nucleotide binding oligomerization domain molecules 17. Toll like receptors are type 1 transmembrane proteins that traffic between the plasma membrane and endosomal vesicles. All TLR share a common architecture, consisting of extracellular leucine rich repeats and a cytoplasmic toll/interleukin 1 receptor (TIR) domain 17,18. Toll like receptors are expressed either on the cell surface or inside intracellular vesicles where they recognize pathogen associated molecular patterns in the extracellular space or in the phagosomes or endosomes. There are 10 and 12 functional TLR members in humans and mice, respectively, each recognizing specific molecular patterns associated with bacteria, mycobacteria, viruses, parasites, and fungi 19. They are primarily responsible for detecting pathogen associated molecular patterns in the extracellular environment. These receptors signal as dimers, differentially recruiting the adaptor proteins Mal (MyD88 adapter like), also called TIRAP (TIR domain containing adaptor protein) and MyD88 (myeloid differentiation primary response gene 88) and/or TRIF (TIR domain containing adaptor inducing IFN β) and TRAM (TRIF related adaptor molecule) 20. A seminal discovery in this regard was the finding that TLR signaling via MyD88 plays a critical role in maintaining epithelial homeostasis and protection from epithelial injury 21. Rakoff Nahoum, et al. using a model of chemical induced intestinal injury 21, showed that Myd88 mice displayed an exacerbated inflammatory phenotype with severe colonic epithelial damage. Toll like receptor 4 is a pattern recognition receptor 22 with primary specificity for bacterial LPS from the gram negative bacterial cell wall 23. The TLR 4 mediated response to LPS is well known for its critical role in innate immune control of gram negative bacterial infection. It was also the first TLR shown to respond to a viral pathogen. Activation of TLR 4 was found to stimulate production of interleukin 10 (IL 10) 8,17,24. It is clear that IL 10 is capable of inhibiting synthesis of proinflammatory cytokines such as interferon γ, IL 2, IL 3, tumor necrosis factor α and granulocyte macrophage colony stimulating factor made by cells such as macrophages and regulatory T cells. It also displays a potent ability to suppress the antigen presentation capacity of antigen presenting cells. Surprisingly, induction of TLR 4 signaling appears to benefit retrovirus, for instance, the murine mammary tumor virus. Firstly, it activates quiescent B cells encouraging cell division, which is necessary for viral genome integration in the host chromosome. Secondly, it promotes secretion of IL 10, an immunosuppressive cytokine that helps the virus persist indefinitely 25. Changes at intestinal tissue during infection The infected individuals suffer from enteropathy that can occur from the acute phase of the infection through advanced disease. It involves diarrhea, increased gastrointestinal inflammation, malabsorption of bile acid and vitamin B12, especially increased intestinal permeability (up to fivefold higher than in healthy controls) 26. Histologically, the GIT enteropathy in relates to inflammatory infiltrates of lymphocytes and damage to the GIT epithelial layer (including crypt hyperplasia, villous atrophy, and villous blunting). These pathological changes may take place in the absence of any detectable bacterial, viral or fungal enteropathogens, which are often associated with enteropathy 15,27 (Table 1). Although the mechanisms that cause the abnormalities in enteropathy are poorly understood, it has been suggested that has a direct virotoxic effect on the enterocyte in early stages. infection directly causes dramatic damage to the GIT that includes substantial disruption of gut microbiota composition with presence of microbes at higher pathogenic potential compared to less aggressive indigenous organisms, massive loss of gut residing CD4 + T cells, and downregulation of GIT gene expression It has also been observed that the accessory protein Tat has an inhibitory effect on glucose uptake in the enterocyte. Furthermore, gp120 has been found to result in increased concentrations of calcium in the enterocyte, which is associated with tubulin de polymerization, and a decrease in epithelial cells ability to maintain ionic balances 15. Gene expression analysis shows that acute infection is accompanied by increased production of proinflammatory cytokines and altered expression of genes related to mucosal repair and regeneration 31. These changes, accompanied by the loss of certain T cell subsets, may lead to impaired barrier function. Altered intestinal permeability is associated with leakage of bacterial products, notably LPS, into plasma 32. In advanced infection, the homeostatic balance between gastrointestinal indigenous bacteria and gut immunity further breaks down and microbes are able to overcome the intestinal barrier and gain the systemic

4 Zhanjun Shu, et al.: How Intestinal Bacteria Can Promote Replication Table 1. Main clinical and histological changes at intestinal tissue during infection Clinical symptoms Histological changes Diarrhea, increased gastrointestinal inflammation Malabsorption of bile acid and vitamin B12 Increased intestinal permeability circulation. Thus, a substantial breach of the anatomo functional gastrointestinal barrier occurs, with progressive failure of mucosal immunity and leakage into the systemic circulation of bacterial byproducts, such as LPS, peptidoglycan, bacterial CpG DNA, flagella, and viral genomes: these molecules can directly stimulate the innate immune system through TIR 1,15,33,34. Brenchley, et al. 28 reported that plasma LPS levels and bacterial ribosomal DNA were elevated in patients with chronic infection as compared with healthy controls. Even after certain treatment, microbial translocation is still not fully controlled by antiviral therapy and is associated with inefficient CD4 + reconstitution 32. It well known that HAART only partially amends GIT antomo functional damage 28,35 and intestinal microbiota, further hampering intestinal homeostasis and sustaining microbial translocation 36,37. Thus, although circulating microbial products have been shown to decrease during HAART, they remain elevated, in turn affecting immune restoration 28,35. Although LPS levels decreased after the initiation of HAART, they remained elevated by twofold compared with those found in uninfected individuals; furthermore, high plasma LPS levels detected in HAART treated individuals were associated with poor CD4 T cell reconstitution in peripheral blood, consistent with the finding that current HAART regimens allow for only partial repair of the gastrointestinal damage that results from infection 15. Inflammatory infiltrates of lymphocytes Damage of the gastrointestinal tract epithelial layer (including crypt hyperplasia, villous atrophy, and villous blunting) Table 2. Impact of on intestinal mucosa at different stages of the infection Early stage Advanced stage After treatment Disruption of gut microbiota composition. Loss of gut residing CD4 + T cells. Downregulation of gastrointestinal tract gene expression. accessory protein Tat has an inhibitory effect on glucose uptake in the enterocyte. gp120 leads to increased concentrations of calcium in the enterocyte. Increased production of proinflammatory cytokines and altered expression of genes related to mucosal repair and regeneration. Bacterial byproducts are able to overcome the intestinal barrier and gain the systemic circulation. Bacterial byproducts remain elevated, in turn affecting immune restoration. A more recent study showed that especially in immunologic non responders among 1 infected, HAART treated patients had the highest level of circulating LPS and persistent T cell hyperactivation compared with 1 infected HAART responders 38. Due to the level of LPS in circulation of blood hardly decreasing, the production of IL 10 stimulated by the TLR 4 mediated response to LPS maintains a certain level, to produce sustained immune tolerance (Table 2). Conclusions and future perspectives The abovementioned growing body of literature demonstrates that intestinal microbiota seemingly plays abetting roles in infection. The intestinal microbiota indirectly promotes enteric virus replication and systemic pathogenesis. To sum up, the delicate yet critical balance between this enormous bacterial population and GIT is gradually destroyed along with incursion (Fig. 1). The leakage into the systemic circulation of bacterial and byproducts such as LPS directly stimulate the innate immune system through toll like receptors. As a result, TLR 4 activation provokes production of IL 10, which mediates immunological tolerance. So a solid deduction is that intestinal microbes may be involved in triggering for replication and transmission of, just like other retroviruses 9. 35

5 AIDS Reviews. 2013;15 36 Gut lumen Epithelial cell Bacteria M-cell Epithelial cell DCs M-cell LPS TLR-4 MyD88 IL-10 TLR-4 MyD88 Promote Suppress LPS LPS Bacteria IL-10 This review likely sheds light on the previously indistinct role of commensal microbiota in retroviral pathogenesis and suggests new approaches for the prevention of replication and transmission. In these ways, keeping the dynamic balance of gut flora and mucosal function may be a first line and hopeful method. Current and emerging researches support the concept that probiotic bacteria can provide specific benefit in 1 infection. Probiotic bacteria have proven active against bacterial vaginosis in 1 positive women and have enhanced growth in infants with congenital 1 infection. In addition, probiotic bacteria may also stabilize CD4 + T cell numbers in 1 infected children and are likely to have protective effects against inflammation and chronic immune activation of the gastrointestinal immune system 39. Secondly, blocking the connection between the LPS and TLR 4 is also a new avenue with great promise. Last but not least, removing intestinal bacteria by using Bacteria DCs antibiotics is a confusing question. To address these questions, it is critical to lay a foundation of basic research to reveal the influence on reproduction and transmission both locally and systemically. References INF-r, IL-2, IL-3, GM-CSF Plasma menbrance Figure 1. Proposed mechanism by which the intestinal bacteria support infection. The delicate balance between this enormous bacterial population and the epithelial barrier is damaged with enterocyte apoptosis along with incursion. The leakage into the systemic circulation of bacterial and byproducts, such as lipopolysaccharide, directly stimulate the innate immune system through toll like receptors. As a result, TLR 4 activation provokes production of interleukin 10, which mediates immunological tolerance, which is involved in triggering for replication and transmission of. LPS: lipopolysaccharide; M cell: microfolded cell; TLR: toll like receptor; IL: interleukin; DC: dendritic cell; INF: interferon; GM CSF: granulocyte macrophage colony stimulating factor. 1. Savage D. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31: Backhed F, Ley R, Sonnenburg J, Peterson D, Gordon J. Host bacterial mutualism in the human intestine. Science. 2005;307: Shu Z, Cao Y, Halmurat U. Gut flora may offer new therapeutic targets for the traditional Chinese medicine enteric dialysis. Expert Opin Ther Targets. 2011;15: Kuss S, Best G, Etheredge C, et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science. 2011;334: Pennisi E. Microbiology. Gut bacteria lend a molecular hand to viruses. Science. 2011;334: Malim M, Emerman M. 1 accessory proteins ensuring viral survival in a hostile environment. Cell Host Microbe. 2008;3: Dittmer U, He H, Messer R, et al. Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity. 2004;20:

6 Zhanjun Shu, et al.: How Intestinal Bacteria Can Promote Replication 8. Jude B, Pobezinskaya Y, Bishop J, et al. Subversion of the innate immune system by a retrovirus. Nat Immunol. 2003;4: Kane M, Case L, Kopaskie K, et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science. 2011;334: van Wijk F, Cheroutre H. Mucosal T cells in gut homeostasis and inflammation. Expert Rev Clin Immunol. 2010;6: Macdonald T, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005;307: Mowat A, Viney J. The anatomical basis of intestinal immunity. Immunol Rev. 1997;156: Moncada D, Kammanadiminti S, Chadee K. Mucin and toll like receptors in host defense against intestinal parasites. Trends Parasitol. 2003;19: Shacklett B, Anton P. infection and gut mucosal immune function: updates on pathogenesis with implications for management and intervention. Curr Infect Dis Rep. 2010;12: Brenchley J, Douek D. infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1: Lakshmanan V, Alter G, Altfeld M, Bhardwaj N. Biology of plasmacytoid dendritic cells and natural killer cells in 1 infection. Curr Opin AIDS. 2007;2: Thompson M, Kaminski J, Kurt Jones E, Fitzgerald K. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3: Kaisho T, Akira S. Toll like receptor function and signaling. J Allergy Clin Immunol. 2006;117: Kawai T, Akira S. Toll like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34: Pang I, Iwasaki A. Control of antiviral immunity by pattern recognition and the microbiome. Immunol Rev. 2012;245: Rakoff Nahoum S, Paglino J, Eslami Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll like receptors is required for intestinal homeostasis. Cell. 2004;118: Medzhitov R, Preston Hurlburt P, Janeway C. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388: Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282: Samarasinghe R, Tailor P, Tamura T, Kaisho T, Akira S, Ozato K. Induction of an anti inflammatory cytokine, IL 10, in dendritic cells after toll like receptor signaling. J Interferon Cytokine Res. 2006;26: Rassa J, Meyers J, Zhang Y, Kudaravalli R, Ross S. Murine retroviruses activate B cells via interaction with toll like receptor 4. Proc Natl Acad Sci USA. 2002;99: Sharpstone D, Neild P, Crane R, et al. Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea. Gut. 1999;45: Batman P, Kotler D, Kapembwa M, et al. enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in /Microsporidia infected jejunal mucosa. AIDS. 2007;21: Brenchley J, Price D, Schacker T, et al. Microbial translocation is a cause of systemic immune activation in chronic infection. Nat Med. 2006;12: Gori A, Tincati C, Rizzardini G, et al. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J Clin Microbiol. 2008; 46: Douek D, Roederer M, Koup R. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med. 2009;60: Sankaran S, George M, Reay E, et al. Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration. J Virol. 2008;82: Merlini E, Bai F, Bellistri G, Tincati C, d Arminio Monforte A, Marchetti G. Evidence for polymicrobic flora translocating in peripheral blood of infected patients with poor immune response to antiretroviral therapy. PLoS One. 2011;6:e Jiang W, Lederman M, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral treated infection. J Infect Dis. 2009; 199: Ferri E, Novati S, Casiraghi M, et al. Plasma levels of bacterial DNA in infection: the limits of quantitative polymerase chain reaction. J Infect Dis. 2010;202: Marchetti G, Cozzi Lepri A, Merlini E, et al. Microbial translocation predicts disease progression of infected antiretroviral naive patients with high CD4+ cell count. AIDS. 2011;25: Brenchley J, Price D, Douek D. disease: fallout from a mucosal catastrophe? Nat Immunol. 2006;7: Paiardini M, Frank I, Pandrea I, Apetrei C, Silvestri G. Mucosal immune dysfunction in AIDS pathogenesis. AIDS Rev. 2008;10: Marchetti G, Bellistri G, Borghi E, et al. Microbial translocation is associated with sustained failure in CD4+ T cell reconstitution in infected patients on long term highly active antiretroviral therapy. AIDS. 2008; 22: Cunningham Rundles S, Ahrne S, Johann Liang R, et al. Effect of probiotic bacteria on microbial host defense, growth, and immune function in human immunodeficiency virus type 1 infection. Nutrients. 2011;3: