HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome

HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome Rachel P. J. Lai 0 1 3 Graeme Meintjes 0 1 2 3 Robert J. Wilkinson 0 1 2 3 0 Department of Medicine, University of Cape Town , Observatory, Cape Town 7925 , South Africa 1 Department of Medicine, Imperial College London , London W2 1PG , UK 2 Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Room 3.03.05, Wolfson Pavilion, Anzio Road, Observatory, Cape Town 7925 , South Africa 3 The Francis Crick Institute, Mill Hill Laboratory , London NW7 1AA , UK Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis. Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium tuberculosis are two major infectious diseases and HIV-1 infection; Tuberculosis; Immune reconstitution inflammatory syndrome; Drug therapy-complications - each was responsible for causing approximately 1.5 million deaths in 2013 [1, 2]. There were an estimated 9.0 million cases of active tuberculosis (TB) in 2013, among which about 1.1 million (13 %) were HIV-1 co-infected [2]. The prevalence of HIV-1 co-infection among TB cases is the highest in Africa, accounting for around 78 % of the total HIV-TB cases. HIV-1 infection and active TB disease individually lead to severe immune impairment and they can also exacerbate the disease progression and pathology of one another. Tuberculosis can cause lymphocytopenia in the absence of HIV-1 or other cause of immunodeficiency [3, 4]. When CD4+ T cells counts were controlled for, HIV-1 patients with active TB disease still have more a rapid course of disease progression and poorer survival rate than those without active TB [5]. Furthermore, people living with HIV-1 are 26–31 times more likely to develop TB than HIV-uninfected individuals [6]. HIV-1 causes functional disruption of the immune response and impairs the host’s ability to control M. tuberculosis infection via several mechanisms (reviewed in [7]). Firstly, HIV-1 replication is higher in stimulated macrophages at the site of M. tuberculosis infection [8, 9], and higher viral loads in bronchoalveolar lavage and in pleural fluid have been observed [10, 11]. Secondly, HIV-1-infected macrophages have reduced secretion of TNF-α that associates with reduced apoptosis in response to M. tuberculosis [12, 13]. While expression of TLR2 and TLR4 are preserved in HIV-1-infected macrophages, TNF-α secretion in response to specific TLR agonists, as well as signal transduction through IRAK-1 and NF-κB nuclear translocation, are significantly reduced [13]. Finally, HIV-1 infects and depletes CD4+ T cells, including those that are M. tuberculosis-specific, resulting in decreased production of IFN-γ, TNF-α and other cytokines that are important in controlling both pathogens [14–18]. Several interventions have been implemented to address the syndemics of HIV-1 and TB. These include routine HIV testing among TB patients, increased coverage of cotrimoxazole and isoniazid preventive therapy in HIV-1infected TB patients and earlier diagnosis of HIVand initiation of antiretroviral therapy (ART) [2]. The increased accessibility of ART has significantly improved the clinical outcome of HIV-1 infected patients and reduces the TB risk by 58–80 % [19]. The positive effects of ART have been described as triphasic, starting with an early and rapid rise of CD45RO+ memory T cells that redistribute from lymphoid tissues into the plasma within the first month of therapy, followed by a reduction in T cell activation and improved CD4+ reactivity to recall HIV-1 antigens, and finally the slower replenishment of the CD45RA+ naïve T cells [20]. In a longitudinal study of coinfected patients sensitized by M. tuberculosis, ART led to an increase in central memory (CD27+CD45RA− and CD27+CCR5−CD4+) T cells by 12 weeks post-treatment, followed by an increase in naïve (CD27+CD45RA+) T cells at 36 weeks [21]. A separate longitudinal study confirmed that the polyfunctional effector memory (CD27−CD45RO+) and terminally differentiated memory (CD27−CD45RO−) CD4+ T cells responsive to mycobacterial purified protein derivative (PPD) were restored 12 months post-ART [22]. Immune reconstitution inflammatory syndrome Although ART has positive effects through suppression of HIV-1 viral load and restoring CD4+ T cell numbers, this rapid restoration of the immune system can also lead to an undesirable complication known as immune reconstitution inflammatory syndrome (IRIS; also known as immune restora (...truncated)