The effect of interrupted anti-retroviral treatment on the reconstitution of memory and naive T cells during tuberculosis treatment in HIV patients with active pulmonary tuberculosis

Background: The reconstitution of cellular immune components contributes to clinical outcome of HIV and Mycobacterium tuberculosis (MTB) infection. Interruption of anti-retroviral therapy (ART) could lead to perturbations in reconstitution of T cells in HIV/ tuberculosis (TB) patients. Objectives: To ascertain the effect of interrupted ART on reconstitution of CD4+ and CD8+ T sub-sets in TB patients.Methods: Participants with HIV (CD4>350 cells/μL) and TB were recruited under a larger phase 3 open label randomised controlled clinical trial. The CD45RO and CD62L markers were measured on CD4+ and CD8+ cells by flow cytometry. Samples were analysed at baseline, 3, 6, 12 months.Results: There was a significant increase of naive CD8+ cells (p = 0.003) and a decrease in effector CD8+ cells (p = 0.004) among participants in ART/TB treatment arm during the first 6 months. Withdrawing ART led to naive CD8+ cells reduction (p=0.02) to values close to baseline. An increase of naive CD8+ cells after 6 months of TB treatment in TB alone treatment arm (p=0.01) was observed. A trend towards increment of naive CD4+ sub sets in either treatment arms was observed.Conclusion: Interrupting ART alters CD8+ but not CD4+ sub-sets in patients with less advanced HIV infection and TB.Keywords: Interrupted anti-retroviral treatment, memory and naive T cells, HIV patients, active pulmonary tuberculosis

The effect of interrupted anti-retroviral treatment on the reconstitution of memory and naive T cells during tuberculosis treatment in HIV patients with active pulmonary tuberculosis.

Background: The reconstitution of cellular immune components contributes to clinical outcome of HIV and Mycobacterium tuberculosis (MTB) infection. Interruption of anti-retroviral therapy (ART) could lead to perturbations in reconstitution of T cells in HIV/ tuberculosis (TB) patients. Objectives: To ascertain the effect of interrupted ART on reconstitution of CD4+ and CD8+ T sub-sets in TB patients. Methods: Participants with HIV (CD4>350 cells/\ub5L) and TB were recruited under a larger phase 3 open label randomised controlled clinical trial. The CD45RO and CD62L markers were measured on CD4+ and CD8+ cells by flow cytometry. Samples were analysed at baseline, 3, 6, 12 months. Results: There was a significant increase of naive CD8+ cells (p = 0.003) and a decrease in effector CD8+ cells (p = 0.004) among participants in ART/TB treatment arm during the first 6 months. Withdrawing ART led to naive CD8+ cells reduction (p=0.02) to values close to baseline. An increase of naive CD8+ cells after 6 months of TB treatment in TB alone treatment arm (p=0.01) was observed. A trend towards increment of naive CD4+ sub sets in either treatment arms was observed. Conclusion: Interrupting ART alters CD8+ but not CD4+ sub-sets in patients with less advanced HIV infection and TB

Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4+ T Cell Activation via Toll-Like Receptors 1 and 2▿

The success of Mycobacterium tuberculosis as a pathogen relies on its ability to regulate the host immune response. M. tuberculosis can manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role of M. tuberculosis molecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules in M. tuberculosis lysate responsible for costimulation of primary human CD4+ T cells. In the absence of APCs, activation of memory CD4+ T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4+ T cells can use TLR2/TLR1 heterodimers to directly respond to M. tuberculosis products. M. tuberculosis lipoproteins induced NF-κB activation in CD4+ T cells in the absence of TCR co-engagement. Thus, TLR2/TLR1 engagement alone by M. tuberculosis lipoprotein triggered intracellular signaling, but upregulation of cytokine production and proliferation required co-engagement of the TCR. In conclusion, our results demonstrate that M. tuberculosis lipoproteins LprG and LpqH participate in the regulation of adaptive immunity not only by inducing cytokine secretion and costimulatory molecules in innate immune cells but also through directly regulating the activation of memory T lymphocytes

Longitudinal TST measurements among HHC.

<p>TST were placed at study enrollment and every 3-month course of INH preventive therapy and post-conversion TST was placed 12 months following each subject's initial conversion event. Following measurement of post-conversion TST, subjects were classified as either stable converters or reverters. Shown are mean TST measurements (mm) ± 1 SD for all eligible study participants at study enrollment (baseline), conversion, and post-conversion time points (A). As shown in Panel B (numbers in boxes indicate number of conversions per time point), subjects with stable conversions were more likely to experience their initial conversion soon following study entry (mean time to conversion, 4.1 months) while reverters experienced their initial conversion later (mean time to conversion 7.2 months; p = 0.03).</p

Tuberculin Skin Test Reversion following Isoniazid Preventive Therapy Reflects Diversity of Immune Response to Primary <i>Mycobacterium tuberculosis</i> Infection

<div><p>Rationale</p><p>Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent <i>Mycobacterium tuberculosis</i> (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.</p><p>Objectives</p><p>To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion.</p><p>Methods</p><p>Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion <i>vs.</i> reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT.</p><p>Results</p><p>Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters.</p><p>Conclusions</p><p>TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.</p></div

Demographic and clinical characteristics of HHC with TST conversion.

<p>Demographic and clinical characteristics of HHC with TST conversion.</p

Longitudinal WB-IGRA results among HHC.

<p>Whole blood was obtained from a subset of eligible subjects at study enrollment (baseline) and time of initial TST conversion. WB-IGRA were performed using Mtb Ag85B (A) and whole Mtb H37Ra (B) as T cell stimulus. Boxes indicate the interquartile ranges, horizontal lines transecting boxes indicate medians, and whiskers indicate highest and lowest values. At study entry (baseline), no significant differences were noted between reverters and stable converters for either stimulus. At the time of conversion, subjects with stable conversion produced significantly more IFN-γ than reverters in response to both Mtb Ag85B and whole Mtb H37Ra (A, B). Moreover, IFN-γ production significantly increased among stable converters between enrollment and conversion, while there were no significant changes noted for reverters. Statistical comparison between groups was performed using Wilcoxon rank sum test, and comparison with groups performed with Wilcoxon sign-rank test (p< 0.05 considered significant).</p

Epidemiologic Measures of TB exposure burden.

<p>Epidemiologic Measures of TB exposure burden.</p