Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

AbstractSince the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied. We hypothesized that there is a common mechanism underlying IRIS pathogenesis and investigated a patient group with IRIS related to different pathogens. Functional and phenotypic characterization of PBMC samples was performed by polychromatic flow cytometry after in vitro stimulation with relevant antigenic preparations. In most patients, IRIS events were characterized by the robust increase of preexisting polyfunctional, highly differentiated effector CD4+ T-cell responses that specifically targeted the antigens of the underlying co-infection. T-cell responses to HIV-1 or other underlying infections were not affected and did not differ between IRIS and non-IRIS patients. These data suggest that patients with IRIS do not have a generalized T-cell dysfunction; instead, IRIS represents a dysregulated CD4+ T-cell response against residual opportunistic infection antigen. These studies were registered at www.clinical-trials.gov as NCT00557570 and NCT00286767.

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Role of CD4+ and CD8+ T-Cell Responses against JC Virus in the Outcome of Patients with Progressive Multifocal Leukoencephalopathy (PML) and PML with Immune Reconstitution Inflammatory Syndrome

Journal of Virology ◽

10.1128/jvi.02506-10 ◽

2011 ◽

Vol 85 (14) ◽

pp. 7256-7263 ◽

Cited By ~ 89

Author(s):

S. Gheuens ◽

E. Bord ◽

S. Kesari ◽

D. M. Simpson ◽

R. T. Gandhi ◽

...

Keyword(s):

T Cell ◽

Progressive Multifocal Leukoencephalopathy ◽

Immune Reconstitution Inflammatory Syndrome ◽

Immune Reconstitution ◽

Jc Virus ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Inflammatory Syndrome

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Loss of Preexisting Immunological Memory Among Human Immunodeficiency Virus–Infected Women Despite Immune Reconstitution With Antiretroviral Therapy

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz678 ◽

2019 ◽

Vol 222 (2) ◽

pp. 243-251 ◽

Cited By ~ 2

Author(s):

Archana Thomas ◽

Erika Hammarlund ◽

Lina Gao ◽

Susan Holman ◽

Katherine G Michel ◽

...

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

Immune Reconstitution ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Memory ◽

Cell Memory ◽

Cell Responses ◽

Immunodeficiency Virus

Abstract Background It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections. Methods We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA). Results There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24–108 years; P = .001). Conclusions Despite antiretroviral therapy–associated improvement in CD4+ T-cell counts (nadir, <200/μL; >350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.

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Regulatory T Cell Abnormalities Associated with Aberrant CD4+ T Cell Responses in Patients with Immune Reconstitution Disease (IRD)

Clinical Immunology ◽

10.1016/j.clim.2007.03.211 ◽

2007 ◽

Vol 123 ◽

pp. S14-S15

Author(s):

Nabila Seddiki

Keyword(s):

T Cell ◽

Regulatory T Cell ◽

Immune Reconstitution ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

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Tuberculosis (TB)-associated immune reconstitution inflammatory syndrome in TB-HIV co-infected patients in Malaysia: prevalence, risk factors, and treatment outcomes

Sexual Health ◽

10.1071/sh14093 ◽

2014 ◽

Vol 11 (6) ◽

pp. 532 ◽

Cited By ~ 3

Author(s):

Hong Yien Tan ◽

Yean Kong Yong ◽

Sin How Lim ◽

Sasheela Ponnampalavanar ◽

Sharifah F. S. Omar ◽

...

Keyword(s):

Risk Factors ◽

T Cell ◽

Treatment Outcomes ◽

Immune Reconstitution Inflammatory Syndrome ◽

Immune Reconstitution ◽

Cd4 T Cell ◽

Cell Recovery ◽

Hiv Patients ◽

Pathogen Load ◽

Inflammatory Syndrome

Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication of antiretroviral therapy (ART) in countries with high rates of endemic TB, but data from South-East Asia are incomplete. Identification of prevalence, risk factors and treatment outcomes of TB-IRIS in Malaysia was sought. Methods: A 3-year retrospective study was conducted among TB-HIV co-infected patients treated at the University of Malaya Medical Centre. Simple and adjusted logistic regressions were used to identify the predictors for TB-IRIS while Cox regression was used to assess the influence of TB-IRIS on long-term CD4 T-cell recovery. Results: One hundred and fifty-three TB-HIV patients were enrolled, of whom 106 had received both anti-TB treatment (ATT) and ART. The median (IQR) baseline CD4 T-cell count was 52 cells μL–1 (13–130 cells μL–1). Nine of 96 patients (9.4%) developed paradoxical TB-IRIS and eight developed unmasking TB-IRIS, at a median (IQR) time of 27 (12–64) and 19 (14–65) days, respectively. In adjusted logistic regression analysis, only disseminated TB was predictive of TB-IRIS [OR: 10.7 (95% CI: 1.2–94.3), P = 0.032]. Mortality rates were similar for TB-IRIS (n = 1, 5.9%) and non-TB-IRIS (n = 5, 5.7%) patients and CD4 T-cell recovery post-ART was not different between the two groups (P = 0.363). Conclusion: Disseminated TB was a strong independent predictor of TB-IRIS in Malaysian HIV-TB patients after commencing ART. This finding underscores the role of a high pathogen load in the pathogenesis of TB-IRIS; so interventions that reduce pathogen load before ART may benefit HIV patients with disseminated TB.

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