Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study.

Background: Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. Methods: We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. Results: MMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro. Conclusions: MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS

Outcomes in HIV-Infected Adults With Tuberculosis at Clinics With and Without Co-Located HIV Clinics in Botswana

SETTING Gaborone, Botswana. OBJECTIVE To determine if starting anti-tuberculosis treatment at clinics in Gaborone without co-located human immunodeficiency virus (HIV) clinics would delay time to highly active antiretroviral therapy (HAART) initiation and be associated with lower survival compared to starting anti-tuberculosis treatment at clinics with on-site HIV clinics. DESIGN Retrospective cohort study. Subjects were HAART-naïve, aged ≥21 years with pulmonary tuberculosis (TB), HIV and CD4 counts ≤250 cells/mm3 initiating anti-tuberculosis treatment between 2005 and 2010. Survival at completion of anti-tuberculosis treatment or at 6 months post-treatment initiation and time to HAART after anti-tuberculosis treatment initiation were compared by clinic type. RESULTS Respectively 259 and 80 patients from clinics without and with on-site HIV facilities qualified for the study. Age, sex, CD4, baseline sputum smears and loss to follow-up rate were similar by clinic type. Mortality did not differ between clinics without or with on-site HIV clinics (20/250, 8.0% vs. 8/79, 10.1%, relative risk 0.79, 95%CI 0.36–1.72), nor did median time to HAART initiation (respectively 63 and 66 days, P = 0.53). CONCLUSION In urban areas where TB and HIV programs are separate, geographic co-location alone without further integration may not reduce mortality or time to HAART initiation among co-infected patients

The complex relationship between human immunodeficiency virus infection and death in adults being treated for tuberculosis in Cape Town, South Africa

Background Despite recognised treatment strategies, mortality associated with tuberculosis (TB) remains significant. Risk factors for death during TB treatment have been described but the complex relationship between TB and HIV has not been fully understood. Methods A retrospective analysis of all deaths occurring during TB treatment in Cape Town, South Africa between 2009 and 2012 were done to investigate risk factors associated with this outcome. The main risk factor was HIV status at the start of treatment and its interaction with age, sex and other risk factors were evaluated using a binomial regression model and thus relative risks (RR) are reported. Results Overall in the 93,133 cases included in the study 4619 deaths (5 %) were recorded. Across all age groups HIV-positive patients were more than twice as likely to die as HIV-negative patients, RR = 2.19 (95 % CI: 2.03–2.37). However in an age specific analysis HIV-positive patients 15–24 and 25–34 years old were at an even higher risk of dying than HIV-negative patients, RR = 4.82 and RR = 3.76 respectively. Gender also modified the effect of HIV- with positive women having a higher risk of death than positive men, RR = 2.74 and RR = 1.94 respectively. Conclusion HIV carries an increased risk of death in this study but specific high-risk groups pertaining to the impact of HIV are identified. Innovative strategies to manage these high risk groups may contribute to reduction in HIV-associated death in TB patients

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice

Analysis of the bonding nature of molecular orbitals through a one-electron partitioning of electronic energy

A virial partitioning of the electronic energy into contributions from individual electrons enables a quantitative estimate of the bonding nature or molecular orbitals. A bonding index for molecular orbitals is proposed. Numerical results arc reported for H2O, CO, HCHO and LiCN

Valency and molecular structure

Valency is defined for each molecular orbital. The molecular orbital valency values are shown to be a good measure of the bonding nature of the molecular orbital. Comparisons are made with photoelectron spectral studies and Mulliken overlap population analysis. The variation of molecular valency and molecular orbital valency with bond angle is studied. It is found that for all the molecules presently considered, energy is linearly related to valency and that the molecular valency reaches a maximum at the equilibrium bond angle. It is also shown that the molecular orbital valency can serve as a quantitatively reliable ordinate for Mulliken-Walsh diagrams