TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB

Abstract

Objective To investigate the impact of tuberculosis (TB)-associated immune reconstitution syndrome (IRIS) upon immunological recovery and the T cell compartment after initiation of TB and antiretroviral therapy (ART). Design and methods We prospectively evaluated T cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n=154) of highly immunosuppressed HIV+ patients with TB from the CAMELIA randomized clinical trial. We compared findings from patients who developed TB-IRIS to findings from patients who did not develop TB-IRIS. Data were evaluated with mixed effect linear regression, Kaplan-Meier estimates, and Wilcoxon rank sum tests, and q-values were calculated to control for multiple comparisons. Results Development of TB-IRIS was associated with significantly greater pre-ART frequencies of HLA-DR+CD45RO+CD4+, CCR5+CD4+, OX40+CD4+, and Fas+ effector memory (EM) CD8+ T cells, and significantly elevated levels of plasma IL-6, IL-1β, IL-8, and IL-10 and viral load. Post-ART initiation, EM CD4+ and Fas+ EM CD4+ T cell frequencies significantly expanded, and central memory (CM) CD4+ T cell frequencies significantly contracted in patients who experienced TB-IRIS. By week 34 post-TB treatment initiation, EM/CM CD4+ T cell ratios were markedly higher in TB-IRIS versus non-TB-IRIS patients. Conclusions A distinct pattern of pre-ART T cell and cytokine markers appear to poise the immune response to develop TB-IRIS. Experience of TB-IRIS is then associated with long-term remodeling of the CD4+ T cell memory compartment towards an EM-dominated phenotype. We speculate that these pre- and post-ART TB-IRIS-associated immune parameters may contribute to superior immune control of TB/HIV co-infection and better clinical outcome.

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

“…We found minimal evidence to support the hypothesis that higher pre-ART levels of cellular immune activation (PD-1 [28,37], HLA-DR, and CD38 [12]) increased risk of subsequent TB-IRIS. These findings are similar to several other investigations [14,16] and are generally consistent with our previous report documenting reduced pre-ART systemic inflammation in those who later developed TB-IRIS [15].…”

“…Furthermore, we found no enrichment in late differentiation stage CD4 + T-cells in TB-IRIS. We were able to compare paradoxical (and not unmasking) IRIS cases and controls in the setting of similar times to ART initiation after tuberculosis diagnosis, thereby eliminating a major potential confounder associated with higher levels of immune activation at ART initiation [7,11,12,38]. Our data cannot elucidate why some individuals recovered polyfunctional responses more rapidly than others.…”

“…With the World Health Organization advocating early ART during tuberculosis treatment in highly immunosuppressed HIV/tuberculosis-coinfected patients [8], the incidence of TB-IRIS will likely rise [4]. Immunologically, higher pre-ART levels of immune activation and rapid increases in tuberculosis-specific interferon gamma (IFN-γ)-producing cells after ART initiation in HIV-infected adults have been associated with development of TB-IRIS [7,[9][10][11][12]. However, in several recent studies, levels of pre-ART immune activation were actually lower in TB-IRIS patients vs controls [13][14][15], and multiple reports have indicated that patients without TB-IRIS may also have robust increases in levels of pathogen-specific immune responses on ART [16,17].…”

HIV infection and immune activation

“…The granulocytic activity of NK cells was also described as important predictor of paradoxical TB IRIS [31]. In a recent study, the role of T cells was further explored by Haridas et al who found that high pre-ART T cell frequencies of HLA-DR, CD45RO, CCR5 and OX40 expressing CD4 T cells, and Fas effector memory CD8 T cells were associated significantly with TB-IRIS development [32]. Interestingly, after ART treatment initiation, the CD4 T cell memory was skewed towards effector-memory phenotype [32].…”

“…In a recent study, the role of T cells was further explored by Haridas et al who found that high pre-ART T cell frequencies of HLA-DR, CD45RO, CCR5 and OX40 expressing CD4 T cells, and Fas effector memory CD8 T cells were associated significantly with TB-IRIS development [32]. Interestingly, after ART treatment initiation, the CD4 T cell memory was skewed towards effector-memory phenotype [32]. In another study, it was postulated that low CD8+ T cell activation (HLA-DR+/CD38+) could be a predisposing factor of both early and late onset TB-IRIS events and that late but not early onset IRIS showed a shift from memory to effector CD8+ and CD4+ T cells after ART initiation [33].…”