Expansion and productive HIV-1 infection of Foxp3 positive CD4 T cells at pleural sites of HIV/TB co-infection.

Background: CD4 T-cells expressing Foxp3 are expanded systemically during active tuberculosis (TB) regardless of HIV-1 co-infection. Foxp3 CD4 T cells are targets of HIV-1 infection. However, expansion of HIV-1 infected Foxp3 CD4 T cells at sites of HIV/TB co-infection, and whether they contribute to promotion of HIV-1 viral activity is not known.

Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease.

Systemic immune activation is critical to the pathogenesis of HIV-1 disease, and is accentuated in HIV/TB co-infected patients. The contribution of immune activation at sites of HIV/TB co-infection to viral activity, CD4 T cell count, and productive HIV-1 infection remain unclear. In this study, we measured markers of immune activation both in pleural fluid and plasma, and in T cells in pleural fluid mononuclear cell (PFMC) and peripheral blood mononuclear cell (PBMC) in HIV/TB co-infected subjects.

Induces Expansion of Foxp3 Positive CD4 T-cells with a Regulatory Profile in Tuberculin Non-sensitized Healthy Subjects: Implications for Effective Immunization against TB.

Objective: Infection by MTB or exposure to MTB constituents is associated with intense microbial stimulation of the immune system, through both antigenic and TLR components, and induction of a milieu that is rich in pro-inflammatory/anti-inflammatory cytokines. Here, we addressed the basis of induced regulatory T-cell (iT-reg) expansion in response to MTB stimulation, in the absence of prior T cell antigen responsiveness.

Methods: PBMC from HIV-1 un-infected TST negative and TST positive control subjects were stimulated by virulent MTB H37Rv lysate (L), a French press preparation of MTB that includes all bacterial components.

Productive HIV-1 infection is enriched in CD4(-)CD8(-) double negative (DN) T cells at pleural sites of dual infection with HIV and Mycobacterium tuberculosis.

A higher human immunodeficiency virus 1 (HIV-1) viral load at pleural sites infected with Mycobacterium tuberculosis (MTB) than in peripheral blood has been documented. However, the cellular source of productive HIV infection in HIV-1/MTB-coinfected pleural fluid mononuclear cells (PFMCs) remains unclear. In this study, we observed significant quantities of HIV-1 p24(+) lymphocytes in PFMCs, but not in peripheral blood mononuclear cells (PBMCs).

CD4 T-cell cytokine correlates of diagnostic tests for latent tuberculous infection in HIV-1-infected subjects.

Setting: Public human immunodeficiency virus (HIV) clinic and tuberculosis (TB) clinics in Kampala, Uganda.

Objective: To examine TB-specific CD4 T-cell single and polyfunctional cytokine correlates of clinical diagnostic tests for latent tuberculous infection (LTBI) in HIV-1-infected subjects.

Design: Thirty antiretroviral therapy-naïve HIV-1-infected adults without active TB disease underwent clinical tuberculin skin test (TST), interferon-gamma release assay (IGRA), and in vitro flow cytometry analysis on cells stimulated with purified protein derivative (PPD) and TB antigens early secreted antigenic target 6 + culture filtrate protein 10 (EC) for frequencies of interleukin (IL) 2, IL-17, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) expressing cells.

CD4+ T cell polyfunctional profile in HIV-TB coinfection are similar between individuals with latent and active TB infection.

CD4+ T cell counts of HIV-infected individuals with pulmonary TB (PTB) are higher than with other opportunistic infections suggesting that progression to PTB is not merely due to T cell depletion but also dysfunction. There are limited data examining T cell functional signatures in human HIV-TB co-infection particularly in PTB which accounts for about 80% of active TB disease overall. We examined a cohort of HIV-infected anti-retroviral naïve individuals in Kampala, Uganda, a TB endemic area using multiparametric flow cytometry analysis to determine IFN-γ, IL-2, IL-17, and TNF-α production in CD4+ memory T cell subsets.

Short Communication: Expression of APOBEC3G and Interferon Gamma in Pleural Fluid Mononuclear Cells from HIV/TB Dual Infected Subjects.

Sites of HIV/TB coinfection are characterized by increased HIV-1 replication and a TH1 profile. However, expression of HIV-1 restriction factors, such as APOBEC3G (A3G) in situ, is unknown. Using an RT-profiler focused on genes related to HIV-1 expansion, we examined pleural fluid mononuclear cells (PFMCs) from patients with HIV/TB coinfection in comparison to HIV-uninfected patients with TB disease.

Comparison of MGIT and Myco/F lytic liquid-based blood culture systems for recovery of Mycobacterium tuberculosis from pleural fluid.

The specificities and sensitivities of the Bactec mycobacterial growth indicator tube (MGIT) system for the recovery of Mycobacterium tuberculosis from pleural fluid are not statistically different than those of the Myco/F lytic liquid culture system. The time to positivity is shorter in the MGIT system (12.7 versus 20.

Short communication: circulating plasma HIV-1 viral protein R in dual HIV-1/tuberculosis infection.

Circulating free HIV-1 viral protein R (Vpr) is found in up to one third of subjects with HIV-1 infection. Free Vpr presumably shares some of the immunopathogenic effects of cell-associated Vpr. Here we assessed Vpr in plasma and pleural fluid from HIV/tuberculosis (TB) dually infected subjects with pleural TB and from plasma of patients with pulmonary HIV/TB.

Role of protease inhibitor 9 in survival and replication of Mycobacterium tuberculosis in mononuclear phagocytes from HIV-1-infected patients.

Objective And Design: Predisposition to opportunistic infections by Mycobacterium tuberculosis (MTB) is a concomitant of HIV-1 infection and occurrence of tuberculosis is independent of circulating CD4(+) T-cell count in HIV-1-infected patients. Infection of mononuclear phagocytes from healthy individuals by virulent MTB is associated with expression of the antiapoptotic molecule protease inhibitor 9 (PI-9), and PI-9 contributes to successful parasitism of macrophages by MTB. Here we studied the contribution of PI-9 to successful MTB infection of monocytes from HIV-1-infected patients.

Effect of Nadir CD4+ T cell count on clinical measures of periodontal disease in HIV+ adults before and during immune reconstitution on HAART.

Background: The contribution of HIV-infection to periodontal disease (PD) is poorly understood. We proposed that immunological markers would be associated with improved clinical measures of PD.

Methods: We performed a longitudinal cohort study of HIV-infected adults who had started highly active antiretroviral therapy (HAART) <2 years.

Systemic immune activation and microbial translocation in dual HIV/tuberculosis-infected subjects.

Background: Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis.

Objective: To understand the role of systemic immune activation and microbial translocation in HIV/tuberculosis dually infected patients over the full spectrum of HIV-1 immunodeficiency, we studied circulating sCD14 and lipopolysaccharide (LPS) and their relationship to HIV-1 activity.

Methods: Two cohorts of HIV/tuberculosis subjects defined by CD4 T-cell count at time of diagnosis of tuberculosis were studied: those with low (<350/μL) and those with high (≥ 350/μL) CD4 T-cell count.

Inhibition of Mycobacterium tuberculosis-induced signalling by transforming growth factor-β in human mononuclear phagocytes.

Tuberculosis (TB) is associated with excessive production and bioactivation of transforming growth factor bets (TGF-β) in situ. Here, modification of expression of components of plasminogen/plasmin pathway in human monocytes (MN) by inhibitors of TGF-β signalling was examined. Smad3 siRNA effectively inhibited TGF-β-induced urokinase plasminogen activator receptor (uPAR).

Induction of serine protease inhibitor 9 by Mycobacterium tuberculosis inhibits apoptosis and promotes survival of infected macrophages.

Our recent microarray analysis of infected human alveolar macrophages (AMs) found serine protease inhibitor 9 (PI-9) to be the most prominently expressed of a cluster of apoptosis-associated genes induced by virulent Mycobacterium tuberculosis. In the current study, we show that induction of PI-9 occurs within hours of infection with M. tuberculosis H37Rv and is maintained through 7 days of infection in both AMs and blood monocytes.

Polyfunctional Mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB.

Pleural tuberculosis (TB) is a common presentation of Mycobacterium tuberculosis (MTB) infection, and despite spontaneous resolution remains a strong risk factor for reactivation pulmonary TB in a majority of individuals. This study was undertaken to further understand the characteristics of immune cells at sites of pleural TB. A significant shift toward memory CD4+ T cells with an effector phenotype and away from naïve CD4+ T cells in pleural fluid as compared to blood mononuclear cells was found.

Activation of P-TEFb at sites of dual HIV/TB infection, and inhibition of MTB-induced HIV transcriptional activation by the inhibitor of CDK9, Indirubin-3'-monoxime.

At sites of Mycobacterium tuberculosis (MTB) infection, HIV-1 replication is increased during tuberculosis (TB). Here we investigated the role of positive transcription elongation factor (P-TEFb), comprised of CycT1 and CDK9, as the cellular cofactor of HIV-1 Tat protein in transcriptional activation of HIV-1 in mononuclear cells from HIV-1-infected patients with pleural TB. Expression of CycT1 in response to MTB was assessed in mononuclear cells from pleural fluid (PFMC) and blood (PBMC) from HIV/TB patients with pleural TB, and in blood monocytes (MN) from singly infected HIV-1-seropositive subjects.

A prospective cohort study of periodontal disease measures and cardiovascular disease markers in HIV-infected adults.

The determinants of HIV-associated cardiovascular disease (CVD) are not well understood. Periodontal disease (PD) has been linked to CVD but this connection has not been examined in HIV infection. We followed a cohort of HIV-infected adults to ascertain whether PD was associated with carotid artery intima media thickness (IMT) and brachial artery flow-mediated dilation (FMD).

Distinct cytokine and regulatory T cell profile at pleural sites of dual HIV/tuberculosis infection compared to that in the systemic circulation.

Pleural tuberculosis (TB) remains a common presentation of Mycobacterium tuberculosis (MTB) infection in HIV/TB dually infected subjects, and both cellular and acellular components of the pleural milieu promote HIV-1 replication; however, they remain uncharacterized. Using cytokine array of pleural fluid and real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunophenotype analysis, pleural fluid mononuclear cells (PFMC) were compared to systemic counterparts [i.e.

Characterizing traditionally defined periodontal disease in HIV+ adults.

Background: Results have varied from previous studies examining the level and extent of periodontal disease (PD) in HIV-1 infected (HIV+) adults. These studies used different methodologies to measure and define PD and examined cohorts with divergent characteristics. Inconsistent methodological approaches may have resulted in the underestimation of traditionally-defined PD in HIV+ individuals.

Relationship of immunodiagnostic assays for tuberculosis and numbers of circulating CD4+ T-cells in HIV infection.

Infection with HIV is the greatest risk factor for tuberculosis (TB) in Africa. Tuberculin skin test (TST), QuantiFERON-TB Gold In-Tube (QFT-G-IT) and T-Spot.TB assays were performed in newly diagnosed HIV-infected individuals with and without active TB and in HIV-uninfected subjects at a university outpatient clinic in Kampala, Uganda.

The interaction of monocyte chemoattractant protein-1 and tumour necrosis factor-alpha in Mycobacterium tuberculosis-induced HIV-1 replication at sites of active tuberculosis.

Tuberculosis (TB) is a prominent opportunistic infection in HIV-1-infected subjects and enhances HIV-1 replication. TB is associated with excess monocyte chemoattractant protein (MCP)-1 and tumour necrosis factor (TNF)-alpha activity in situ, both of which are implicated in transcriptional activation of HIV-1. The role of MCP-1 and TNF-alpha in activation of HIV-1 during TB and by Mycobacterium tuberculosis (MTB) in mononuclear cells from HIV-1/TB subjects with pleural TB was examined here.

Induction of HIV type 1 expression correlates with T cell responsiveness to mycobacteria in patients coinfected with HIV type 1 and Mycobacterium tuberculosis.

An in vitro mononuclear cell system to model the microenvironment of coinfection with HIV-1 and Mycobacterium tuberculosis (MTB) was developed. This cellular system was used to assess the interaction of MTB-infected monocytes and T cells from dually infected HIV-1/TB patients with pulmonary tuberculosis (TB). Subjects with higher induction of HIV-1 gag/pol mRNA expression after MTB stimulation had increased MTB-specific T cell IFN-gamma and TNF-alpha production.

Response to M. tuberculosis selected RD1 peptides in Ugandan HIV-infected patients with smear positive pulmonary tuberculosis: a pilot study.

Background: Tuberculosis (TB) is the most frequent co-infection in HIV-infected individuals still presenting diagnostic difficulties particularly in developing countries. Recently an assay based on IFN-gamma response to M. tuberculosis RD1 peptides selected by computational analysis was developed whose presence is detected during active TB disease.

Allicin-induced suppression of Mycobacterium tuberculosis 85B mRNA in human monocytes.

Despite of encountering a robust immune response, Mycobacterium tuberculosis (MTB) successfully survives and persists in the human host. We investigated the early regulation of MTB 85B gene by allicin in MTB-infected human monocytes. During the first 24h of infection, levels of both MTB 85B intracellular mRNA and secreted protein were significantly down-regulated by allicin in a dose-dependent manner, which was mediated by inhibition of glutathione and NF-kappaB pathway.