Immune reconstitution inflammatory syndrome in HIV infection: taking the bad with the good

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1 (2017) 23, doi: /odi Published This article is a U.S. Government work and is in the public domain in the USA All rights reserved INVITED MEDICAL REVIEW Immune reconstitution inflammatory syndrome in HIV infection: taking the bad with the good C-S Wong, ES Richards, L Pei, I Sereti HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID/NIH, Bethesda, MD, USA In this review, we will describe the immunopathogies of immune reconstitution inflammatory syndrome, IRIS. IRIS occurs in a small subset of HIV patient, initiating combination antiretroviral therapy (ART), where immune reconstitution becomes dysregulated, resulting in an overly robust antigen-specific inflammatory reaction. We will discuss IRIS in terms of the associated coinfections: mycobacteria, cryptococci, and viruses. (2017) 23, Keywords: immunology; microbiology; HIV; immune reconstitution; lymphopenia; coinfection Introduction The introduction of ART has transformed HIV infection from a fatal disease to a chronic condition, in which HIV viral replication is suppressed and host immune function is partially restored leading to the improvement of ongoing infections and decreased susceptibility to new ones. In about 10 20% of patients initiating ART, however, immune reconstitution becomes dysregulated, resulting in aberrant inflammation that is directed against an opportunistic infection (French, 2009; Sereti et al, 2010). This immune dysregulation is known as immune reconstitution inflammatory syndrome or IRIS. IRIS can be classified into paradoxical, where a previously diagnosed opportunistic infection worsens following initiation of ART, or unmasking, when initiation of ART initiates the, usually atypical, presentation of a previously undiagnosed opportunistic infection (Barber et al, 2012; Chang et al, 2014). The risk factors for IRIS include severe CD4 lymphopenia, opportunistic infections, and higher HIV viral load at baseline (Muller et al, 2010). Although IRIS can be a self-limiting disease, it has become a considerable burden Correspondence: Irini Sereti, HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID/NIH, 10 Center Drive, Building 10, 11B-07A, Bethesda, MD 20892, USA. Tel: , Fax: , Isereti@niaid.nih.gov Received 26 September 2016; revised 19 October 2016; accepted 20 October 2016 on the management of the HIV epidemic especially in resource-limited countries, associated with high morbidity rate (Muller et al, 2010; Sereti et al, 2010; Chang et al, 2014; Meya et al, 2016). Further research is still needed to provide better biomarkers to predict for IRIS and treatments for prevention or treatment. IRIS was first described in an Australian cohort of immunodeficient HIV patients with worsening Mycobacterium avium intracellulare infections after treatment with zidovudine monotherapy (French et al, 1992); however, a variety of opportunistic infections have been associated with IRIS, including mycobacterial (Mycobacterium avium complex (MAC) and mycobacterium tuberculosis (TB)), fungal (cryptococcal, pneumocystis, Histoplasma), and viral (cytomegalovirus, herpes zoster, herpes simplex, and Kaposi s sarcoma herpesvirus, JC virus) (Domingo et al, 2001; Bower et al, 2005; Lawn et al, 2005; Tan et al, 2009; Haddow et al, 2010). In this review, we will discuss the various opportunistic infections associated with IRIS and their associated immunopathologies. Mycobacterial IRIS The majority of IRIS events are associated with mycobacterial disease causing significant morbidity and mortality given the prevalence of TB worldwide and the frequent coinfection with HIV (Zumla et al, 2015). The two main mycobacterial pathogens that cause IRIS are MAC and TB. MAC-IRIS can occur in 20 49% of HIV patients with CD4 count <50 cells ll 1 (Adams et al, 2014). The incidence of TB-IRIS varies from 8 to 54%, depending on the epidemiological setting and TB prevalence (Narita et al, 1998; Breen et al, 2004; Meintjes et al, 2008; Narendran et al, 2013; Adams et al, 2014). There are two types of TB-associated IRIS in HIV patients who have recently started ART (Meintjes et al 2008). The first, paradoxical TB-IRIS, occurs in patients who have previously been diagnosed with TB and showed clinical improvement with TB therapy before starting ART. The second type, unmasking TB-IRIS, occurs in patients who have not been diagnosed with TB before the initiation of ART and developed active TB within 3 months of starting ART. Clinical presentation of TB-IRIS includes fevers, emerging

2 or worsening lymphadenopathy, worsening radiological features of TB, and pulmonary infiltrate or pleural effusion (Lawn et al, 2005; Meintjes et al, 2008; Muller et al, 2010). Although the immunopathogenesis of mycobacterial IRIS is still not fully understood, ongoing studies have elucidated many aspects of IRIS pathogenesis that could lead to better strategies for prevention and treatment. Numerous studies have shown that CD4 + type I helper (Th1) cells in mycobacterial IRIS patients are highly activated, exhibiting heightened antigen-specificinflammatory responses (Antonelli et al, 2010; Mahnke et al, 2012; Meintjes et al, 2012). IRIS has been associated with increased production of inflammatory cytokines such as IFN-c, TNF-a, and IL-2 by antigen-specific CD4 + T cells during IRIS events. This increase of inflammatory cytokines is driven by antigen-specific CD4 + T cells, while responses to other pathogens remain intact suggesting that there is no global CD4 + T-cell dysfunction (Mahnke et al, 2012). TB-IRIS patients also displayed higher frequencies of effector memory T cells and high levels of activation markers (HLA-DR hi ) and higher proliferation rates (Ki-67 + ) in CD4 + T cells than non-iris patients supporting the conclusion that highly differentiated and activated cells are driving the pathology of IRIS (Antonelli et al, 2010). In addition to CD4 + Th1, cd T cells have also been associated with the pathogenesis of IRIS. An increase of Vd2 + in TCRcd + KIR T cells lacking KIR expression was present at baseline and could be used to distinguish patients who will develop IRIS from those who will not, emphasizing that IRIS is an antigenspecific inflammatory response (Bourgarit et al, 2009). To better dissect the pathways involved in the pathogenesis in IRIS, Barber et al developed a MAC-IRIS mouse model (Antonelli et al, 2010). Using T-cell-deficient (TCRa knockout) mice latently infected with M. avium, Barber et al transferred CD4 + T cells to mimic the post- ART CD4 + reconstitution event in IRIS patients. Wasting disease was observed in TCRa deficient mice infected with M. avium mice post-cd4 + T transfer, but no IRISlike symptoms were observed post-cd4 + transfer in T- cell-replete wild type at the time of M. avium infection, demonstrating the importance of lymphopenia in driving IRIS-associated inflammation. IFN-c was found to be overexpressed in mice with the wasting disease. When CD4 + IFN-c deficient T cells was transferred, the disease phenotype was delayed rather than inhibited, showing that IFN-c plays an important role in the pathogenesis of IRIS, although not required for IRIS initiation. This was further corroborated by the report of a patient with disseminated TB with IFN-c neutralizing autoantibodies who developed a severe paradoxical inflammatory response after TB therapy. This indicates that IFN-c could potentially be essential for controlling TB infection, although not required in the initiation of IRIS (Xie et al, 2016). Lastly, even though lymphopenia is known to increase the risk of developing IRIS after CD4 + T-cell repopulation, it is not a requirement for the reconstitution disease (Antonelli et al, 2010; Barber et al, 2010). Rather, antigen recognition by T cells at the time of CD4 + T repopulation with increased sensitivity and dysregulation of activation seemed to be the main driving force of IRIS. In addition to the activation of adaptive immune responses, different components of the innate immune responses such as monocytes and natural killer (NK) cells have been implicated in the pathogenesis of TB-IRIS. Andrade et al showed that monocytes in TB-IRIS patients were highly activated and produced higher levels of IL-1b, IL-6, and tissue factor, and the expansion and activation of the CD14 ++ CD16 monocyte subset were independently associated with the development of TB-IRIS pre-art (Andrade et al, 2014). In another study by Barber et al, IL-6, a cytokine released mainly by monocytes, was shown to be a key mediator of IRIS (Barber et al, 2014). Increased levels of IL-6 and C-reactive protein were observed at the IRIS event in a cohort of seven MAC-IRIS patients as well as in the MAC-IRIS mouse model. Blockade of both IL-6 and IFN-c further delayed onset of the wasting disease in mice suggesting the crucial role of IL-6 and innate immune responses in IRIS pathology. NK cells are also thought to influence the immunological responses of TB-IRIS (Pean et al, 2012; Wilkinson et al, 2015). Pean et al showed that NK cell degranulation capacity, marked by CD107 expression, could differentiate TB-IRIS from non-iris patients prior to the initiation of ART. High level of degranulation at baseline was found to increase the risk of IRIS in HIV TB coinfected patients (Pean et al, 2012). Wilkinson et al showed that the granule exocytosis pathway might play a role in TB-IRIS pathophysiology (Wilkinson et al, 2015). Increased expression of granzyme B and perforin was observed in a cohort of 64 TB-IRIS patients compared with 34 non-iris patients. Invariant NKT cells were thought to contribute to the production of perforin (Wilkinson et al, 2015). In conclusion, the hyperactivation and dysregulation of cells in both the innate and adaptive immune systems mediate the pathogenesis of IRIS. Understanding IRIS pathogenesis could provide valuable insight in the development of more effective and more specific therapy. Current treatment for mycobacterial IRIS consists of immunosuppressive corticosteroid therapy that could improve clinical symptoms (Meintjes et al, 2010). However, corticosteroids sometimes fail to manage severe IRIS. Blockade of inflammatory cytokines such as TNF-a had been shown to improve the clinical condition of mycobacterial IRIS patients who were not responding to corticosteroid treatment (Hsu et al, 2016). Another challenge specific to treating TB-IRIS is the timing of TB therapy and ART. The duration of TB therapy prior to the initiation of ART was shown to have an effect on the development of IRIS with longer TB treatment reducing the complication of IRIS. However, delayed HIV treatment increases the risk of all-cause mortality leading to the recommendation of starting ART early, within 2 weeks, in patients with CD4 counts below 50 cells ll 1 (Abdool Karim et al, 2011; Blanc et al, 2011; Havlir et al, 2011; Manosuthi et al, 2012; Sinha et al, 2012; Mfinanga et al, 2014; Amogne et al, 2015). It is thus anticipated that prevalence of TB-IRIS will increase in HIV 823

3 824 infection, making development of new preventive or treatment strategies more pressing. Cryptococcal IRIS Among the most fatal coinfections in HIV-infected patients is Cryptococcus neoformans, an opportunistic fungal pathogen (Dunn et al, 2007). Within the USA, coinfection with Cryptococcus accounts for nearly 7% of the people with HIV who have CD4 + T-cell counts below 100 cells ll 1 (Dupin et al, 1995; Barber et al, 2012). Despite antifungal therapy and the use of ART, cryptococcal meningitis (CM) remains a significant cause of mortality among HIV-infected patients, especially among those who develop IRIS (Meya et al, 2016). Clinical manifestations of cryptococcal IRIS most commonly affect the central nervous system including meningitis, seizures and CNS cryptococcoma lesions; however, lymphadenopathy, pleurisy and pneumonitis have also been described (Muller et al, 2010; Barber et al, 2012; Andrade et al, 2013, Andrade et al, 2014). Data from the Cryptococcal Optimal ART Timing Cryptococcal Optimal ART Timing (COAT) Trial showed that deferring ART initiation for 5 weeks increased survival rates of patients when compared to those who started ART at 1 2 weeks after the diagnosis of CM (Chang et al, 2014). A possible result of earlier ART initiation may be an increase in inflammatory responses in the CNS, which could negatively affect the survival rate of those starting ART earlier (Chang et al, 2014). To further elucidate the immune responses during HIV-associated CM, Boulware et al examined baseline CSF immune responses in patients with HIV-associated CM were associated and predictive of subsequent IRIS development (Boulware et al, 2014). Most markedly, proinflammatory IL-6 and IFN-c pre-art were associated with improved outcomes, by way of Th1 T-cell responses for Cryptococci clearance (Boulware et al, 2014). Jarvis et al examined cytokine profiles and chemokine responses alongside macrophage activation markers in a study that showed IL-6 and IFN-y to be protective in the context of Cryptococci clearance (Jarvis et al, 2015). Furthermore, they showed that higher CSF chemokine concentrations of MCP-1 and MIP-1a were predictive of IRIS. In a prospective study, Chang et al found that lower CD4 + T-cell responses and higher CD8 + T cell and/or macrophage responses to cryptococcus in the CSF of HIV-infected patients are potential risk factors for C-IRIS (Chang et al, 2014). Recently, Eschke et al developed a mouse model of cryptococcal IRIS using cryptococcus-infected immunodeficient mouse (Rag1 deficient) that was reconstituted with CD4 + T cells as to mimic the increase of T cells post-art (Eschke et al, 2015). Mirroring cryptococcal IRIS patients, these mice developed an overly exuberant inflammatory disease with high levels of IFN-c, IL-6, and TNF-a and highly active CD4 + T cells and myeloid cells. Interestingly, this proinflammatory disease was independent of IFN-c, and IFN-c / CD4 + T cells still led to IRIS development (Barber et al, 2010). This demonstrates how the immunological mechanisms and compartmentalization of infection may lead to divergent immunologic pathways in certain opportunistic pathogens. Viral IRIS The immunopathogenesis of viral-associated IRIS is still unclear. Viruses known to be associated with IRIS include cytomegalovirus (CMV), herpes zoster virus (VZV), herpes simplex virus (HSV), hepatitis B virus (HBV), Human herpesvirus 8 (HHV-8), and JC virus. CMV is a betaherpesvirus that can be transmitted via saliva, sexual contact, breastfeeding, blood transfusion, and organ transplants (Adland et al, 2015). Both HSV and VZV are alpha-herpesviruses that can establish latency in the ganglia (Dunic et al, 2005). HHV-8 is part of the gamma herpesvirus family and is known to cause Kaposi s sarcoma (Cesarman et al, 1995). And finally, JC virus is a polyomavirus that infects oligodendrocytes, which can lead to progressive multifocal leukoencephalopathy (PML) (Beltrami and Gordon, 2014). Hepatitis B virus About 20 25% of patients who are coinfected with HBV and HIV will develop IRIS, or hepatitis flare, related to hepatitis B (Avihingsanon et al, 2012; Andrade et al, 2013), with a sudden increase in liver enzymes (Liaw, 2003). IRIS-associated hepatic flares usually occur within 56 days post-art initiation (Avihingsanon et al, 2012). Although it is difficult to differentiate the pathogenesis of HBV-IRIS and HBV infection alone, it is believed that hepatic damage due to HBV alone is caused by TRAILexpressing NK cells (Dunn et al, 2007). In contrast to hepatic flares associated with HBV infection, HBV-IRIS is thought to be driven by T cells as seen by the enhanced recruitment of T cells to the liver due to the increase of the chemoattractant, CXCL-10 (Crane et al, 2009). In addition, innate immune system biomarkers specifically monocyte-associated factors, such as D-dimer, IL-6, and scd14, are associated with death within 4 years of ART initiation in HIV-HBV coinfected persons (Andrade et al, 2013). Much like mycobacterial and also cryptococcal IRIS, higher antigen load, as seen as higher plasma HBV DNA, increases risk of hepatic flares (Avihingsanon et al, 2012; Andrade et al, 2013). Finally, increased IL-10 levels are also independently associated with hepatic flares (Andrade et al, 2013). IL-10 is hypothesized to be either a compensatory cytokine produced to alleviate the proinflammatory response of the hepatic flare or play a role in suppressing an effective Th1 and Th17 responses resulting in the higher antigen load. Cytomegalovirus The incidence of CMV-IRIS varies from 9.6% up to 64.3% (Urban et al, 2014). Most commonly, CMV-IRIS presents as inflammation (uveitis) in the posterior uveal tract of the eye in patients with inactive CMV retinitis, although gastrointestinal involvement by CMV can lead to other IRIS manifestations such as acute appendicitis (Faldetta et al, 2014; Urban et al, 2014). The symptoms of CMV-IRIS can also be very subtle, with IRIS manifesting as viral reactivation and shedding after initiation of ART; this was observed to occur in 78% of women coinfected with HIV, HSV-2, and CMV in Uganda (Gianella et al, 2015). Like HBV-IRIS, CMV-IRIS is thought to be

4 Figure 1 Oral Kaposi s sarcoma as an unmasking IRIS manifestation. Patient had no oral or skin lesions when starting ART with a CD4 count of 15 cells ll 1 and plasma HIV-RNA copies ml 1. After 4 weeks of ART, his CD4 count had increased to 77 cells ll 1, HIV- RNA had dropped to 128 copies ml 1, and he had mucosal purple lesions typical of KS Box 1 Cytokines and growth factors Interleukin-2 (IL-2) Interleukin-10 (IL-10) Interleukin-6 (IL-6) Monocyte protein (MCP-1) Tumor necrosis factor alpha (TNF-a) Vascular endothelial growth factor (VEGF) Functions Activate lymphocytes: drive T-cell proliferation, active NK cells Anti-inflammatory cytokine, associated with T regulatory cells Proinflammatory cytokine that is important in regulating the acute phase of response Chemokine that regulates recruitment and infiltration of monocytes, memory T cells and NK cells Proinflammatory cytokine that is involved in a range of biological activities including apoptosis, cell proliferation, and differentiation Angiogenic factor. Under normal physiological conditions, VEGF is important in bone formation, hematopoiesis, wound healing, and development T-cell-driven, as seen in the high predominance of T cells in the epiretinal membrane of patients with uveitis due to CMV-IRIS (Kosobucki et al, 2004), although innate immunity also may be another contributing factor as seen by the high levels of IL-10 and IL-6 in the eyes of these patients (Schrier et al, 2006). Human herpesvirus 8 HHV-8 or KS-associated herpesvirus is the virus causing Kaposi s sarcoma and also two rare types of B-cell lymphomas known as primary effusion lymphoma and HIVassociated multicentric Castleman s disease (Cesarman et al, 1995; Dupin et al, 1995; Karcher and Alkan, 1995). KS-IRIS usually presents as cutaneous or mucosal lesions anywhere on the body (Figure 1) (Papagatsia et al, 2009) (Jussila et al, 1998). About 6.6% of HIV patients develop KS-IRIS with the first 2 months of initiation of ART (Bower et al, 2005; Papagatsia et al, 2009) (Figure 1). KS-IRIS has been associated with mortality, particularly when there is visceral involvement (Papagatsia et al, 2009). Much like other subtypes of IRIS, KS-IRIS patients have higher levels of Th1-associated cytokines, IFN-c and TNF-a, suggesting a CD4 + T cell-driven inflammation. CD8 + T cells specific for HHV-8 also increase during IRIS; however, their role in driving IRIS is unknown (Krown, 2003). Baseline antigen load (HHV8 plasma levels) is a valuable predictor of KS-IRIS (Cattelan et al, 2016). It has been suggested that KS progression could be the result of a KSHV-specific immune response due to the initiation of ART. Latently, infected cells are exposed to the proinflammatory environment due to ART initiation, which facilitates differentiation of these cells into KS-like spindle cells and reactivates HHV-8. HHV-8 can subsequently produce viral IL-6, which upregulates VEGF, inducing angiogenesis initiating the development of a KS lesion (Mesri, 1999; Monini et al, 1999). Herpes zoster virus VZV is a common disease occurring in about 33% of the US population; it is also a very common coinfection in patients with HIV (Buchbinder et al, 1992; Muller et al, 2010). Of the cases of IRIS, 7 12% are associated with VZV-IRIS, which usually presents 8 80 weeks post-art, with peak time of onset around 16 weeks post-art (Domingo et al, 2001; Dunic et al, 2005; French, 2009). VZV-IRIS may present as encephalitis, myelitis, and other CNS-related inflammation, although most cases present with a typical dermatomal rash (shingles) (Buchbinder et al, 1992; Domingo et al, 2001; Dunic et al, 2005). VZV-IRIS has been linked to increases of CD8 + T cells; however, the role of CD8 + T cells driving the pathogenesis is still unknown (Domingo et al, 2001). Given the frequent reactivation of zoster in other immune restoration settings such as bone marrow transplant, further elucidation of the pathogenesis could be helpful in prevention. Conclusion Despite the dramatic improvement of prognosis in HIV infections, patients with severe lymphopenia starting ART are at risk for IRIS, an aberrant inflammatory response that is triggered by underlying copathogens such as TB, MAC, Cryptococcus or KSHV. Although studies have shown critical roles for both CD4 + T cells and innate cells such as monocytes or NK cells, the pathogenesis remains unclear. Better understanding of the pathways involved in IRIS will assist in the development of targeted preventive or therapeutic strategies. Funding This work was supported by the Intramural Research Program of NIAID, NIH. 825

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