Changes in the NK Cell Repertoire Related to Initiation of TB Treatment and Onset of Immune Reconstitution Inflammatory Syndrome in TB/HIV Co-infected Patients in Rio de Janeiro, Brazil—ANRS 12274

Abstract

Tuberculosis (TB) is the most common comorbidity and the leading cause of death among HIV-infected individuals. Although the combined antiretroviral therapy (cART) during TB treatment improves the survival of TB/HIV patients, the occurrence of immune reconstitution inflammatory syndrome (IRIS) in some patients poses clinical and scientific challenges. This work aimed to evaluate blood innate lymphocytes during therapeutic intervention for both diseases and their implications for the onset of IRIS. Natural killer (NK) cells, invariant NKT cells (iNKT), γδ T cell subsets, and in vitro NK functional activity were characterized by multiparametric flow cytometry in the following groups: 33 TB/HIV patients (four with paradoxical IRIS), 27 TB and 25 HIV mono-infected subjects (prior to initiation of TB treatment and/or cART and during clinical follow-up to 24 weeks), and 25 healthy controls (HC). Concerning the NK cell repertoire, several activation and inhibitory receptors were skewed in the TB/HIV patients compared to those in the other groups, especially the HCs. Significantly higher expression of CD158a ( p = 0.025), NKp80 ( p = 0.033), and NKG2C ( p = 0.0076) receptors was detected in the TB/HIV IRIS patients than in the non-IRIS patients. Although more NK degranulation was observed in the TB/HIV patients than in the other groups, the therapeutic intervention did not alter the frequency during follow-up (weeks 2–24). A higher frequency of the γδ T cell population was observed in the TB/HIV patients with inversion of the Vδ2 + /Vδ2 − ratio, especially for those presenting pulmonary TB, suggesting an expansion of particular γδ T subsets during TB/HIV co-infection. In conclusion, HIV infection impacts the frequency of circulating NK cells and γδ T cell subsets in TB/HIV patients. Important modifications of the NK cell repertoire were observed after anti-TB treatment (week 2) but not during the cART/TB follow-up (weeks 6–24). An increase of CD161 + NK cells was related to an unfavorable outcome. Despite the low number of cases, a more preserved NK cell profile was detected in IRIS patients previous to treatment, suggesting a role for these cells in IRIS onset. Longitudinal evaluation of the NK repertoire showed the impact of TB treatment and implicated these cells in TB pathogenesis in TB/HIV co-infected patients.

HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus

“…The median average pairwise distances (APDs) of all proviral sequences was 1.95% (range 0.5%-2.4%), consistent with diverse HIV-1 populations arising after long-term infection (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI138099DS1). Immunophenotyping of PBMCs showed no major differences between donors and healthy HIV-1-negative controls (25)(26)(27)(28)(29)(30)(31)(32) in the frequencies of T cells, B cells, or NK cells or in expression levels of surface activation markers (CD25, CD69, CD38, and CD107a), with the exception of higher HLA-DR expression (Supplemental Table 3), which is consistent with prior observations in HIV-1-positive individuals on effective ART (33).…”

“…Email: jwm1@pitt.edu. (BD Biosciences) was performed on a BD LSRII cytometer according to standard published methods (58), analyzed using FlowJo (BD), and results compared with published results of healthy adults (25)(26)(27)(28)(29)(30)(31)(32).…”

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

“…Concerning natural killer (NK) cells, Pean et al showed that patients with IRIS had a higher proportion of NK cells degranulation levels of these cells were predictive markers of IRIS development among Cambodian TB-HIV co-infected individuals [3]. Our group performed a similar analysis for a subset of patients here included, but no difference was observed in NK degranulation between IRIS and non-IRIS groups [47]. Also, other groups reported elevated frequencies of KIR-γδ T-cells [67] and CD69+ NK cells [68] in TB-IRIS patients during pre-ART, suggesting that these cells may play a role in IRIS-associated pathology.…”

“…Patients' enrolment and study design This is a genetic study nested in two clinical and immunological follow-up studies previously conducted in the Laboratory of AIDS and Molecular Immunology (IOC/FIOCRUZ), which assessed immunological characteristics of TB-HIV co-infected individuals and the risk factors for paradoxical TB/HIV-IRIS [32, 46,47]. The HLA-B, HLA-C and KIR genetic profiles were determined from 162 individuals divided into four groups as follows: Group 1 -individuals infected with HIV-1 and tuberculosis (HIV+/TB+ group, n = 88; 11 of them with IRIS); Group 2 -individuals infected with HIV-1 without diagnosis of TB (HIV-1+ group, n = 24); Group 3 -individuals with tuberculosis and seronegative for HIV-1 infection (TB+ group, n = 24); and Group 4 -healthy volunteers without HIV-1 infection and/or TB (control group, n = 26).…”

Inflammasome genetic variants are associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

“…This study nested two clinical and immunological follow-up studies conducted in the Laboratory of AIDS & Molecular Immunology (IOC/FIOCRUZ) from 2006 to 2016, as previously described ( da Silva et al., 2013 ; da Silva et al., 2017 ; Giacoia-Gripp et al., 2019 ). All participants signed an informed consent form, and the local ethics committee approved the studies.…”