Tuberculosis After Commencing Antiretroviral Therapy for HIV Infection Is Associated With Elevated CXCL9 and CXCL10 Responses to Mycobacterium tuberculosis Antigens

Oliver, Benjamin G.; Elliott, Julian; Price, Patricia; Phillips, Michael; Cooper, David A.; French, Martyn A.

doi:10.1097/qai.0b013e31826445ef

Cited by 15 publications

(13 citation statements)

References 31 publications

(46 reference statements)

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“…However, both these studies demonstrated that IFN-γ responses to PPD increased after ART in both TB-IRIS patients and controls, as demonstrated in the study reported here. Assaying CXCL10 in plasma from whole-blood IGRAs demonstrates larger T-cell responses to RD1 antigens before and 4 weeks after ART in patients who develop TB-IRIS, but the difference is small and not as clear as in patients who develop TB after commencing ART 27. Taken together, the findings of this and previous studies suggest that IFN-γ responses to PPD and, to a lesser extent RD1 antigens, increase in all HIV patients with treated TB after ART is commenced but that the increase is larger in patients with TB-IRIS and is detectable by ELISpot assays, 14–16,19 intracellular flow cytometry (this study), or assay of IFN-γ in supernatants from cultures of antigen-stimulated PBMCs (this study), but not IGRAs 20,21.…”

Section: Discussionmentioning

confidence: 98%

TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

Vignesh

Kumarasamy

Lim

et al. 2013

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background The role of T-cell responses against Mycobacterium tuberculosis antigens in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is unclear. Methods Peripheral blood mononuclear cells from 45 HIV patients with treated TB, of whom 12 developed TB-IRIS, were collected at weeks 0, 2, and 6 of antiretroviral therapy (ART). Production of interferon-γ (IFN-[γ]) and interleukin-2 by T cells after stimulation with purified protein derivative (PPD) or early secretory antigenic target-6 (ESAT-6) and T-cell expressions of CCR5 and CXCR3 were assessed by flow cytometry. IFN-γ and CXCL10 were assayed by enzyme-linked immunosorbent assay. Results TB-IRIS patients had higher proportions of PPD- and ESAT-6–reactive IFN-γ+CD4+ and CD3+CD4- T cells at weeks 0, 2, and 6. IFN-γ levels were also higher in peripheral blood mononuclear cell culture supernatants at all times with PPD but only at weeks 2 and 6 with ESAT-6. There were few differences for interleukin-2. CXCL10 levels in supernatants after PPD and ESAT-6 stimulation were only higher at week 6. CXCR3+/CCR5+CD4+ T cells were higher at week 2, and CCR5+CD4+ T cells were higher at week 6. Conclusions TB-IRIS is associated with Th1 responses against M. tuberculosis antigens by CD4+ and CD3+CD4- T cells that are present before ART and amplified afterward. It is unclear if these cause immunopathology or reflect a high pathogen load.

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Section: Discussionmentioning

confidence: 98%

TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

Vignesh

Kumarasamy

Lim

et al. 2013

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Among humans, males are more susceptible to protozoan, fungal, bacterial, and viral infections than females and are more likely to die from these infections [26]–[28]. Surprisingly CXCL10 has been implicated in several diseases including CM [7], [12], [15]–[17], Toxoplasma gondii [29], tuberculosis [30]–[35], candidiasis [36], West Nile Virus [37], [38], hepatitis B virus [19], [39], and HIV [40] suggesting that CXCL10 may confer susceptibility to these infections.…”

Section: Discussionmentioning

confidence: 99%

CXCL10 Gene Promoter Polymorphism -1447A>G Correlates with Plasma CXCL10 Levels and is Associated with Male Susceptibility to Cerebral Malaria

et al. 2013

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The risk factors for cerebral malaria (CM) and the wide variation in clinical manifestations of malaria are poorly understood. Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. Increased plasma and cerebrospinal fluid levels of CXCL10 were tightly associated with fatal CM in Indian and Ghanaian patients. In the present study, we hypothesized that in a subset of malaria patients, CM susceptibility is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection. Following extensive bioinformatics analyses, two reported single nucleotide polymorphisms in the CXCL10 promoter (−135G>A [rs56061981] and −1447A>G [rs4508917]) were identified among 66 CM and 69 non-CM Indian patients using PCR-restriction fragment length polymorphism assay. Individuals with the −1447(A/G) genotype were susceptible to CM (adjusted odds ratio [AOR] = 2.60, 95% CI = 1.51–5.85, p = 0.021). In addition, individuals with the −1447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the −1447(A/A) genotype. Stratifying patients according to gender, the observed association of CM with over expression of CXCL10 were more pronounced in males than in female patients (AOR = 5.47, 95% CI = 1.34–22.29, p = 0.018). Furthermore, −135G>A polymorphism conferred a decreased risk of CM among males (AOR = 0.19, 95% CI = 0.05–0.78, p = 0.021). Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of CM. These results suggest that the −1447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of CM outcomes particularly in males.

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“…This should be confirmed in clinical studies. Immune-based diagnostic tests, such as IGRAs, may have a role in the diagnosis of subclinical TB (23, 25), and their use should be evaluated further. Understanding the mechanism of LTBI is essential.…”

Section: Mycobacterium Tuberculosis Co-infectionmentioning

confidence: 99%

HIV and co‐infections

Chang

Crane

Zhou

et al. 2013

Immunological Reviews

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145

101

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Summary Despite significant reductions in morbidity and mortality secondary to availability of effective combination antiretroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub-Saharan Africa where rates of opportunistic co-infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV-infected patients globally. These include co-infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus (HBV), hepatitis C virus (HCV), and Plasmodium falciparum. Specifically, we review the natural history of each co-infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co-infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co-infection via vaccination. Finally, we discuss the opportunities and gaps for future research.

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Tuberculosis After Commencing Antiretroviral Therapy for HIV Infection Is Associated With Elevated CXCL9 and CXCL10 Responses to Mycobacterium tuberculosis Antigens

Abstract: Tuberculosis after commencing ART is associated with increased CXCL10 and, to a lesser extent, CXCL9 responses to M. tuberculosis antigens. Assessment of antigen-induced CXCL10 responses to RD1 antigens may assist in the prediction and diagnosis of ART-TB.

Cited by 15 publications

References 31 publications

TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

CXCL10 Gene Promoter Polymorphism -1447A>G Correlates with Plasma CXCL10 Levels and is Associated with Male Susceptibility to Cerebral Malaria

HIV and co‐infections

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