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Gut microbes out of control in HIV infection
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Nature Medicine Dec 2006 - 12, 1351 - 1352
Barton F Haynes
The author is at the Duke Human Vaccine Institute, Center for HIV-AIDS Vaccine Immunology, Duke University School of Medicine, Circuit Drive, Durham, North Carolina 27710, USA.
HIV-1 infection results in chronic activation of the immune system-a process that is thought to contribute to T-cell depletion and progression to AIDS. Chronic activation is now suggested to occur through a breakdown of the mucosal barrier and stimulation of immune cells by microbial products (pages 1365-1371).
A hallmark of pathogenic simian immuno- deficiency virus (SIV) and HIV-1 infections is persistent systemic immune activation-leading to exhausted immune responses, pro-inflammatory cytokine production and uncontrolled viral replication in activated T cells. In HIV-1 infection, the degree of immune activation is a better predictor of disease progression than plasma viral load1. However, the cause of immune activation in chronic HIV-1 infection is not known.
In this issue, Brenchley et al.2 address this question. The authors provide evidence that a cause of immune activation in chronic HIV infection may be breakdown of the gut mucosal barrier and stimulation of immune cells by microbial products, a process termed microbial translocation. They suggest that microbial translocation occurs following damage to the surface of the gut mucosa and induction of mucosal CD4+ T-cell depletion by HIV-1, a main aspect of disease pathogenesis2.
In support of their conclusions, the authors show that plasma lipopolysaccharide (LPS), a quantitative indicator of microbial translocation, is elevated in people with chronic HIV-1 infection. Plasma LPS is biologically active, its levels decrease following antiretroviral treatment, and its levels are not elevated in nonhuman primates with nonpathogenic SIV infection2.
In healthy adults, the mucosa-associated lymphoid tissue (MALT) contains 80% of all immune cells within the body and constitutes the largest mammalian lymphoid organ system. The MALT has three main functions: (i) to protect mucous membranes from invasive pathogens; (ii) to prevent uptake of foreign antigens from food, commensal organisms, and airborne pathogens and particulate matter; and (iii) to prevent pathologic immune responses against foreign antigens if they cross the mucosal barriers of the body3.
MALT immune cells are continuously bathed in foreign proteins and commensal bacteria, and they must select those pathogenic antigens that must be eliminated, or at least prevented from accessing the systemic circulation. MALT contains anatomically defined foci of immune cells in the intestine, tonsil, appendix and peribronchial areas that are inductive sites for mucosal immune responses. From these sites, immune T and B cells migrate to effector sites in mucosal parenchyma and exocrine glands where mucosal immune cells eliminate pathogens and pathogen-infected cells (Fig. 1).
Key components of the MALT include specialized follicle-associated epithelial cells that take up antigens and deliver them to dendritic cells or other antigen presenting cells (APCs). Effector cells in MALT include B cells producing anti-pathogen neutralizing antibodies of secretory IgA as well as IgG isotypes, TCR- and TCR- T cells producing cytokines, and CD4 T-helper and CD8 cytotoxic T cells that respond to pathogen-infected cells.
Recent studies have shown that commensal gut and other mucosal bacteria are vital to the health of the human immune system3, 4. Normal commensal flora induce anti-inflammatory events in the gut and protect epithelial cells from pathogens through Toll-like receptors (TLRs) and other pathogen-recognition signaling. When the gut is depleted of normal commensal flora, the immune system becomes abnormal, with loss of T-helper type 1 (TH1) T-cell function4. Restoration of the normal gut flora can re-establish the balance in T-helper cell ratios characteristic of the normal immune system.
When the gut barrier is intact, luminal antigen traffic across the mucosa is highly attenuated, and when pathogens are present, a self-limited, protective MALT immune response eliminates the pathogen. However, when the gut barrier breaks down, as occurs following irradiation, in graft-versus-host disease and in certain autoimmune diseases, immune responses to commensal flora antigens have been suggested to cause bowel inflammation such as in Crohn disease. Uncontrolled MALT immune responses to food antigens, such as gluten, can cause celiac disease3.
Brenchley et al. postulated earlier this year that microbial translocation following gut injury and immune cell depletion in acute HIV-1 infection is a cause of immune activation in chronic HIV-1 infection5. They now provide initial evidence for this hypothesis by showing elevated levels of plasma LPS and the monocyte LPS receptor CD14 in individuals with HIV-1. In addition, they found that monocytes from these individuals were refractory to ex vivo LPS stimulation, implying that monocytes had been stimulated with LPS in vivo. Moreover, HIV-1-infected plasma, cultured with normal immune cells, resulted in in vitro T- and B-cell activation and monocyte stimulation. The authors speculate that multiple products of microbial translocation may participate in immune activation inducing RNA, DNA, bacterial peptidoglycan and flagellin, as well HIV-1 itsel2.
These new data and several other insights into HIV-1 pathogenesis all point to CD4+ T-cell destruction in the gastrointestinal tract as a key focus of new research. Other insights include the following observations: much of the total body (and therefore gut) CD4 T-cell loss occurs in the earliest stages of acute HIV-1 infection6, 7; plasma viral loads are high in nonpathogenic SIV infections, yet immune activation is low8, 9; the number of central memory cells are the best correlate of survival in SIV-challenged, SIV-vaccinated monkeys10, 11; and vaccine induction of anti-SIV T cells can preserve the CD4 memory T-cell pool following SIV challenge, showing that a T-cell SIV vaccine can protect against SIV-induced gut T-cell loss11.
That the level of gut immune cell destruction and microbial translocation may determine the rate of progression to AIDS has important implications for HIV-1 treatment. Plasma markers of microbial translocation may be useful for following disease progression, and early screening for acute HIV-1 infection may be needed in order to institute early antiretroviral treatment to preserve immune cell levels.
This study is provocative and its finding of an association between HIV-1 infection and microbial translocation is robust. Yet it is important to keep in mind that the authors have not yet directly shown that microbial translocation causes immune activation in HIV-1. In this regard, there are important issues to explain in future research. First, in nonpathogenic SIV infection of sooty mangabeys, gut CD4+ cells are depleted, yet LPS plasma levels are not elevated. Second, immune activation is present in acute HIV-1 infection, yet, again, plasma LPS levels are not elevated.
In addition, it is important to learn if bacterial translocation in HIV-1 infection is caused by damage to immune cells, epithelial cells or both. TCR- T cells have been implicated in maintaining the integrity of interstitial epithelial cell tight junctions and preventing microbial translocation12. It is important to learn the status of TCR- T cells in the earliest stages of acute HIV-1 infection. Finally, the observations of Brenchley et al. emphasize the notion that understanding the events that lead to mucosal immune system depletion and damage will be critical to developing insight into what an HIV-1 vaccine must do to be effective in preventing HIV-1 transmission. Mucosal SIV infections that destroy gut CD4 T cells are associated with a delay in the induction of mucosal antiviral host responses13.
A successful preventive HIV-1 vaccine must prime the host for the ability to mount innate and adaptive antiviral immune responses within hours to several days after HIV-1 infection in order to prevent substantial MALT loss and allow for control and possibly elimination of HIV-1. Understanding the events that lead to mucosal damage and immune cell depletion in acute HIV-1 infection is the first step to achieving that goal.
REFERENCES
1. Giorgi, J.V. et al. J. Infect. Dis. 179, 859-870 (1999). | Article | PubMed | ISI | ChemPort |
2. Brenchley, J.M. et al. Nat. Med. 12, 1365-1371 (2006).
3. Macdonald, T.T. & Monteleone, G. Science 307, 1920-1925 (2005). | Article | PubMed | ISI | ChemPort |
4. Fiocchi, C. N. Engl. J. Med. 353, 2078-2080 (2005). | Article | PubMed | ChemPort |
5. Brenchley, J.M., Price, D.A. & Douek, D.C. Nat. Immunol. 7, 235-239 (2006). | Article | PubMed | ChemPort |
6. Veazey, R.S. et al. Science 280, 427-431 (1998). | Article | PubMed | ISI | ChemPort |
7. Mehandru, S. et al. J. Exp. Med. 200, 761-770 (2004). | Article | PubMed | ISI | ChemPort |
8. Diop, O.M. et al. J. Virol. 74, 7538-7547 (2000). | Article | PubMed | ChemPort |
9. Dunham, R. et al. Blood 108, 209-217 (2006). | Article | PubMed | ChemPort
10. Letvin, N.L. et al. Science 312, 1530-1533 (2006). | Article | PubMed | ChemPort |
11. Mattapallil, J.J. et al. J. Exp. Med. 203, 1533-1541 (2006). | Article | PubMed | ChemPort |
12. Dalton, J.E. et al. Gastroenterology 131, 818-829 (2006). | Article | PubMed | ChemPort |
13. Abel, K. et al. J. Virol. 79, 12164-12172 (2005). | Article | PubMed | ISI | ChemPort |
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