Dataset Information

The metabolic consequences of HIV/TB co-infection.

ABSTRACT:

Background

The synergy between the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis during co-infection of a host is well known. While this synergy is known to be driven by immunological deterioration, the metabolic mechanisms that contribute to the associated disease burden experienced during HIV/tuberculosis (TB) co-infection remain poorly understood. Furthermore, while anti-HIV treatments suppress viral replication, these therapeutics give rise to host metabolic disruption and adaptations beyond that induced by only infection or disease.

Methods

In this study, the serum metabolic profiles of healthy controls, untreated HIV-negative TB-positive patients, untreated HIV/TB co-infected patients, and HIV/TB co-infected patients on antiretroviral therapy (ART), were measured using two-dimensional gas chromatography time-of-flight mass spectrometry. Since no global metabolic profile for HIV/TB co-infection and the effect of ART has been published to date, this pilot study aimed to elucidate the general areas of metabolism affected during such conditions.

Results

HIV/TB co-infection induced significant changes to the host's lipid and protein metabolism, with additional microbial product translocation from the gut to the blood. The results suggest that HIV augments TB synergistically, at least in part, contributing to increased inflammation, oxidative stress, ART-induced mitochondrial damage, and its detrimental effects on gut health, which in turn, affects energy availability. ART reverses these trends to some extent in HIV/TB co-infected patients but not to that of healthy controls.

Conclusion

This study generated several new hypotheses that could direct future metabolic studies, which could be combined with other research techniques or methodologies to further elucidate the underlying mechanisms of these changes.

SUBMITTER: Herbert C

PROVIDER: S-EPMC10436461 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

The metabolic consequences of HIV/TB co-infection.

Herbert Chandré C Luies Laneke L Loots Du Toit DT Williams Aurelia A AA

BMC infectious diseases 20230818 1

<h4>Background</h4>The synergy between the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis during co-infection of a host is well known. While this synergy is known to be driven by immunological deterioration, the metabolic mechanisms that contribute to the associated disease burden experienced during HIV/tuberculosis (TB) co-infection remain poorly understood. Furthermore, while anti-HIV treatments suppress viral replication, these therapeutics give rise to host metabolic disru ...[more]

PMID: 37592227

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Project description:BackgroundCurrent diagnostics are inadequate to meet the challenges presented by co-infection with Mycobacterium tuberculosis (Mtb) and HIV, the leading cause of death for HIV-infected individuals. Improved characterization of Mtb/HIV coinfection as a distinct disease state may lead to better identification and treatment of affected individuals.MethodsFour previously-published TB and HIV co-infection related datasets were used to train and validate multinomial machine learning classifiers that simultaneously predict TB and HIV status. Classifier predictive performance was measured using leave-one-out cross validation on the training set and blind predictive performance on multiple test sets using area under the ROC curve (AUC) as the performance metric. Linear modelling of signature gene expression was applied to systematically classify genes as TB-only, HIV-only or combined TB/HIV.ResultsThe optimal signature discovered was a 10-gene random forest multinomial signature that robustly discriminated active tuberculosis (TB) from other non-TB disease states with improved performance compared with previously published signatures (AUC: 0.87), and specifically discriminated active TB/HIV co-infection from all other conditions (AUC: 0.88). Signature genes exhibited a variety of transcriptional patterns including both TB-only and HIV-only response genes and genes with expression patterns driven by interactions between HIV and TB infection states, including the CD8+ T-cell receptor LAG3 and the apoptosis-related gene CERKL.ConclusionsBy explicitly including distinct disease states within the machine learning analysis framework, we developed a compact and highly diagnostic signature that simultaneously discriminates multiple disease states associated with Mtb/HIV co-infection. Examination of the expression patterns of signature genes suggests mechanisms underlying the unique inflammatory conditions associated with active TB in the presence of HIV. In particular, we observed that dysregulation of CD8+ effector T-cell and NK-cell associated genes may be an important feature of Mtb/HIV co-infection.

Project description:In Cape Town, the roll-out of antiretroviral therapy (ART) has increased over the last decade with an estimated coverage of 63% of HIV- positive patients in 2013. The influence of ART on the characteristics of the population of HIV-positive patients presenting to the primary care TB programme is unknown. In this study, we examined trends in CD4 count distribution, ART usage and treatment outcomes among HIV-positive TB patients in Cape Town from 2009 to 2013.Data from the electronic TB register on all newly registered drug-sensitive TB patients ?18 years were analyzed retrospectively. Descriptive statistics were used to compare baseline characteristics, the CD4 count distribution and TB treatment outcomes both by year of treatment and ART status at the start of TB treatment. Survival analyses were used to assess the change in mortality risk during TB treatment over time, stratified by ART status at start of TB treatment.118,989 patients were treated over 5 years. HIV prevalence among TB patients decreased from 50.9% in 2009 to 49.0% in 2013. The absolute number of HIV-positive TB cases declined by 13.2% between 2010 and 2013. More patients entered the TB programme on ART in 2013 compared to 2009 (30.0% vs 9.9%). Among these, the CD4 count distribution showed a year by year shift to higher CD4 counts. In 2013, over 75% of ART-naïve TB patients still had a CD4 count <?350 cells/mm3. ART initiation among ART-naive patients increased from 37.0 to 77.7% and TB case fatality declined from 7.4 to 5.2% (p?<?0.001). In multivariate analysis a decrease in TB mortality was most strongly associated with CD4 count (Adjusted HR 0.82 per increase of 50 cells/mm3, 95% CI: 0.81-0.83, p?<?001) and the initiation of ART during TB treatment (Adjusted HR 0.39, 95% CI: 0.35-0.42, p?<?0.001).Comprehensive changes in the ART and TB treatment programmes resulted in incremental increases in ART coverage for HIV-positive TB patients and a subsequent decrease in TB case fatality due to increased ART uptake in HIV-positive ART-naïve patients. However TB still remained a major presenting opportunistic infection with the majority of cases occurring at low CD4 counts.

Dataset Information

The metabolic consequences of HIV/TB co-infection.

Background

Methods

Results

Conclusion

Publications

The metabolic consequences of HIV/TB co-infection.

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