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Correlates for Disease Progression and Prognosis During Concurrent HIV/TB Infection

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Correlates for Disease Progression and Prognosis During Concurrent HIV/TB Infection International Journal of Infectious Diseases (2007) 11, 289—299 http://intl.elsevierhealth.com/journals/ijid REVIEW Correlates for disease progression and prognosis during concurrent HIV/TB infection Joel Fleury Djoba Siawaya a,*, Morten Ruhwald b, Jesper Eugen-Olsen c, Gerhard Walzl a a Immunology Unit, Department of Biomedical Sciences, DST/NRF Center of Excellence in Biomedical TB Research, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa b Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark c Clinical Research Unit, Copenhagen University Hospital, Hvidovre, Denmark Received 9 August 2006; received in revised form 9 November 2006; accepted 1 February 2007 Corresponding Editor: Salim S. Abdool Karim, Durban, South Africa KEYWORDS Summary Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) are TB; both life-threatening pathogens in their own right, but their synergic effects on the immune HIV; system during co-infection markedly enhance their effect on the host. This review focuses on the Concurrent infection; bidirectional interaction between HIV and Mtb and discusses the relevance of sputum smear Immune correlates; examination, CD4+ counts, viral load at baseline and after initiation of anti-retroviral therapy, as Progression; well as additional existing and new potential immune correlates of disease progression and Prognosis prognosis. These markers include b2-microglobulin, neopterin, tumor necrosis factor receptor II (TNFRII), CD8+/CD38+, soluble urokinase plasminogen activator receptor (suPAR) and CXCL10 (or IP-10). # 2007 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Synergistic effect of concurrent HIV and TB to reactivation and progression to active tuberculosis (TB).3,4 infection For example, the lifetime risk of progressing to active TB in people with latent infection with Mtb (LTBI) is about 5%.5 This escalates to well over 10%2,4 with an annual rate between 7% The influence of concurrent human immunodeficiency virus and 10%, when there is concurrent HIV infection.6 Additionally, (HIV) and Mycobacterium tuberculosis (Mtb) infection on dis- the risk of mortality due to concurrent HIV/Mtb is twice that of ease progression of both individual diseases has been clearly HIV infection alone.7 established during the past years. Mtb infection represents the leading cause of mortality in HIV-infected patients,1,2 whereas HIV is a very strong factor predisposing Mtb-infected subjects Interference with the ability of dendritic cells to direct the adaptive immune response * Corresponding author. Tel.: +27 21 9389399; fax: +27 21 9389476. Key concepts in the immunologic interplay of Mtb and HIV E-mail address: [email protected] (J.F. Djoba Siawaya). infection are summarized in Figure 1. LTBI is a dynamic state 1201-9712/$32.00 # 2007 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2007.02.001 290 J.F. Djoba Siawaya et al. Figure 1 Key concepts of immunopathogenesis of latent TB. In brief, cytokines drive the interaction between CD4+ T-cells and infected macrophages. Stable latent TB infection requires dominance of Th1 over Th2 for effective containment of the infection within granulomas. HIV infection results in T-cell depletion but also in a switch from Th1 to Th2 dominance, thus enabling progression to active disease. The uptake of HIV through DC-SIGN enables transinfection of CD4+ T-cells and leads to both functional defects and loss of CD4+ cells that are required for an effective immune response against Mtb. DC, dendritic cell; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; Th, T helper cell; Treg, regulatory T-cell; TGF,transforming growth factor; DC-SIGN, DC-specific intercellular adhesion molecule-3-grabbing nonintegrin; Mtb, Mycobacterium tuberculosis. between mycobacterium and host immunity. Infected macro- nonintegrin (DC-SIGN)-dependent uptake of HIV facilitates T- phages and dendritic cells (DCs) process and present myco- cell transinfection.11—13 Mycobacteria also shed molecules bacterial and viral antigens to CD4+ and CD8+ T-cells and interacting with DCs and macrophages through DC-SIGN and other lymphocyte subsets like regulatory T-cells, gd and this has been shown to stimulate secretion of the anti-inflam- natural killer (NK) cells. Processed peptides together with matory cytokine IL-10, thereby suppressing DC function and macrophage/DC-derived interleukin (IL)-12 favor T helper maturation.14 This could have severe consequences in the case cell 1 (Th1) differentiation and secretion of interferon- g of concurrent HIVand Mtb infection as the conjugated effect of (IFN-g), IL-2 and tumor necrosis factor-a (TNF-a), which are the two pathogens will supposedly increase not only DC- believed to be protective.8 Although DCs are seen as crucial dependent T-cell transinfection but also minimize the ability in the production of an effective adaptive immune response of the host to respond adequately to pathogens, thereby due to their ability to carry antigens to lymphoid tissue where enhancing their survival and dissemination. interactions with CD4+ T-cells occur,9,10 it has been reported Substantial evidence exists that DCs can influence the that DC-specific intercellular adhesion molecule-3-grabbing immune response and outcome of infections although the Correlates for disease progression and prognosis in HIV/TB infection 291 mechanisms are not fully understood. Several types of DCs depletion of CD4+ T-cells caused by HIV activity increases have been described in humans and include the following: the the likelihood of Mtb reactivation and disease.35 HIV infection myeloid DCs (DC1) that elicit the Th1 response in the pre- has also been shown to negatively impact on TB recurrence sence of IL-12, and the plasmacytoid DCs (DC2) that elicit a and treatment failure.36,37 It is the underlying cause of the Th2 response when IL-4 is present.15 It has been shown that paradoxical reaction38,39 and presumed to increase the like- the presence of IL-10 and the absence of IL-12 may lead to lihood for developing TB drug resistance.40 Th2 polarization by default.16 This may be one of the means by which Mtb-infected DCs shift the Th-cell balance from the Tuberculosis immune reconstitution required Th1 response to a more deleterious Th2 type response. inflammatory syndrome (TB IRIS) Cytokine dysregulation drives immunopathology TB IRIS is recognized in two different clinical situations. during concurrent HIV and Mtb infection Unrecognized active TB may be unmasked early after initiation of highly active antiretroviral therapy (HAART) when the TNF-a and IFN-g are key cytokines in granuloma formation development of abscesses containing acid-fast bacilli enables 41 that contain TB infection; however, pro-inflammatory cyto- diagnosis. Alternatively, a known TB patient on anti-TB kines and especially TNF-a will, in excess, lead to severe treatment may develop worsening of the clinical picture after 42 tissue destruction and caseating necrosis.17 The sustained the introduction of HAART. TB IRIS usually develops within 2— 43 containment of stable LTBI is based on the balance between 8 weeks of initiation of HAART, although much later pre- 42 protective responses (pro-inflammatory) and suppressive sentations have been described. A universally accepted responses (anti-inflammatory) to limit immunopathology. clinical definition has not been established but a combination The dominant Th1 cell activation is under the regulation of the development of new symptoms, new clinical signs, new of other T-cell subsets. Polarized Th2 sets secrete IL-4, IL- radiological findings, and special investigations may be needed 10 and IL-13 and thereby inhibit the Th1-mediated pro- to secure this diagnosis. Symptoms developing after the onset inflammatory and tissue-destructive response. CD4+CD25+ of HAART include fever, feeling acutely unwell, and increased regulatory T-cells favor Th2 skewing by augmenting suppres- cough or dyspnea. The development of new clinical signs may sive reactions and promoting negative feedback on Th1 involve lymph node enlargement, occurrence of skin lesions or cells.18 Secretion of IL-4 in active TB patients has always development of subcutaneous or muscle abscesses. Radiolo- been looked at as an indicator of Th2 cell activity.19 There is gical signs include new or enlarging mediastinal lymph nodes evidence that increased IL-4 secretion enhances TNF-a toxi- (or abdominal nodes as seen by ultrasound or computed city and fibrosis20 and promotes TNF-a-mediated apoptosis in tomography) and increased pulmonary infiltrates or appear- 41,42 Mtb activated lymphocytes. IL-4 is therefore involved in the ance of pleural effusions. An increase in the size of a immunopathology of TB infection21 and its presence has been tuberculin skin test reaction, a drop in viral load and an associated with the extent of tuberculosis disease.22—24 increase in CD4+ counts are characteristic results from special 42 In the case of concurrent HIV and Mtb infection the IL-4/ investigations associated with IRIS. Further research is TNF-a interaction could exacerbate the situation, as the needed to enable the establishment of reliable diagnostic depletion of T-cells would make the host vulnerable to HIV criteria and algorithms. progression. The discovery of IL-4d2, an IL-4 splice variant The risk for development of TB IRIS is higher in patients and IL-4 antagonist, has brought new insight into the concept receiving treatment for TB and antiretroviral treatment 38,39 of immune regulation and problems with its assessment. simultaneously, and higher in patients with disseminated 38 Commonly used immunoassays for IL-4 do not differentiate TB. The immunopathology of TB IRIS is based on restoration between IL-4 and its splice variant, and it is now clear that IL- of mycobacteria-specific T-cells after induction of antiretro- 4 levels have to be interpreted together with IL-4d2 expres- viral therapy. Clinical presentation of IRIS corresponds to sion levels.
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