Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment

Abstract

The reconstitution of Mycobacterium tuberculosis antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in a high tuberculosis endemic area is described. Restoration of the antigen-specific CD4 T-cell subsets mirrored the overall CD4 T-cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known M. tuberculosis sensitization determined by interferon-γ release assay, 12/23 participants had no M. tuberculosis-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T-cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.

Antiretroviral treatment-induced decrease in immune activation contributes to reduced susceptibility to tuberculosis in HIV-1-TB co-infected persons

“…Our more targeted analysis of soluble plasma biomarkers in the context of Mtb sensitisation during ART, using QFT supernatants, shows a decrease in antigen specific IL-beta and IL-1alpha as well as MCP-1, in line with decreased HIV-1 induced immune activation and inflammation. At the same time, antigen specific IP-10 (Ag-nil) concentrations significantly increased, together with chemokine expressing CD4 T cells, in keeping with memory T cell expansion as we demonstrated previously (7, 10). Overall, our data indicates that the ART- induced decrease in immune activation combined with improved antigen responsiveness may contribute to reduced susceptibility to tuberculosis in HIV-1-TB co-infected persons.…”

“…Overall, the above data support a decrease in HIV-1 induced immune activation and inflammation over the first 6 months of ART, even in the context of Mtb sensitisation. However, to better understand the increase in antigen specific IP-10 (Ag-Nil) concentrations, we evaluated the expression of chemokine receptors CXCR3, CCR4 and CCR6 on the surface of CD4 T cells, using PBMC in a subset of 25 patients from the same cohort, as previously described (10). We found expanding numbers of CD4 T cells expressing CXCR3 (the receptor for IP-10), as well as Due to increased rates of cardiovascular disease among people living with HIV-1, this is an important area to explore in further studies.…”

“…(APC-AF750), CD4 (FITC), CD45RA (BV570), CD27 (BV711), CXCR3 (PE-Cy7), CCR4 (BV510), CCR6 (BV605). Cells were acquired on a BD-Fortessa flow cytometer and analysed using FlowJo as previously described (10).…”

An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa

“…Immune reconstitution was key since we based the HITTIN phenotype on immune assays which are dependent on functioning T-cells. The ability of ART reconstituted CD4 T-cells to produce IFN-γ in response to ESAT-6/CFP-10 remains the same or improves with time on ART, although this is not always fully restored to the same extent as in HIV uninfected persons [35] , [36] , [37] , [38] . Although the ART duration in HITTIN was shorter than that of HIT and previous TB groups, it has been determined that the functional potential of Mtb -antigen specific T-cells can significantly change after only three months on ART [36] .…”

An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa

“…The ability of ART reconstituted CD4 T-cells to produce IFN-γ in response to ESAT-6/CFP-10 remains the same or improves with time on ART, although this is not always fully restored to the same extent as in HIV uninfected persons. [35][36][37][38] Although the ART duration in HITTIN was shorter than that of HIT and previous TB groups, it has been determined that the functional potential of Mtb-antigen specific T-cells can significantly change after only three months on ART. [36] Most studies considered the effect of ART over only a few weeks, but HITTIN identified in this study have been on ART an average of 7 years, making it unlikely that the negative results in IGRA and TST reported here are due to a lack of host ability to produce IFN-γ.…”