Immune variations throughout the course of tuberculosis treatment and its relationship with adrenal hormone changes in HIV-1 patients co-infected with Mycobacterium tuberculosis

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

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A Novel Tuberculosis DNA Vaccine in an HIV-1 p24 Protein Backbone Confers Protection against Mycobacterium tuberculosis and Simultaneously Elicits Robust Humoral and Cellular Responses to HIV-1

Clinical and Vaccine Immunology ◽

10.1128/cvi.05700-11 ◽

2012 ◽

Vol 19 (5) ◽

pp. 723-730 ◽

Cited By ~ 4

Author(s):

Xiaoman Li ◽

Wei Xu ◽

Sidong Xiong

Keyword(s):

Mycobacterium Tuberculosis ◽

T Cell ◽

Dna Vaccine ◽

Cellular Response ◽

Mycobacterial Infection ◽

T Cell Epitopes ◽

Content Type ◽

P24 Protein ◽

Elevated Frequency ◽

Hiv 1

ABSTRACTTuberculosis (TB) caused byMycobacterium tuberculosisremains a major infectious disease worldwide. Moreover, latentM. tuberculosisinfection is more likely to progress to active TB and eventually leads to death when HIV infection is involved. Thus, it is urgent to develop a novel TB vaccine with immunogenicity to bothM. tuberculosisand HIV. In this study, four uncharacterized T cell epitopes from MPT64, Ag85A, Ag85B, and TB10.4 antigens ofM. tuberculosiswere predicted, and HIV-1-derived p24, an immunodominant protein that can induce protective responses to HIV-1, was used as an immunogenic backbone.M. tuberculosisepitopes were incorporated separately into the gene backbone of p24, forming a pP24-Mtb DNA vaccine. We demonstrated that pP24-Mtb immunization induced a strongM. tuberculosis-specific cellular response as evidenced by T cell proliferation, cytotoxicity, and elevated frequency of gamma interferon (IFN-γ)-secreting T cells. Interestingly, a p24-specific cellular response and high levels of p24-specific IgG were also induced by pP24-Mtb immunization. When the protective effect was assessed after mycobacterial challenge, pP24-Mtb vaccination significantly reduced tissue bacterial loads and profoundly attenuated the mycobacterial infection-related lung inflammation and injury. Our findings demonstrated that the pP24-Mtb tuberculosis vaccine confers effective protection against mycobacterial challenge with simultaneously elicited robust immune responses to HIV-1, which may provide clues for developing novel vaccines to prevent dual infections.

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Evaluating the effectiveness of anti-tuberculosis treatment by detecting Mycobacterium tuberculosis 85B messenger RNA expression in sputum

Journal of Infection and Public Health ◽

10.1016/j.jiph.2020.05.016 ◽

2020 ◽

Vol 13 (10) ◽

pp. 1490-1494

Author(s):

Ersan Atahan ◽

Suat Saribas ◽

Mehmet Demirci ◽

Aylin Babalık ◽

Seher Akkus ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Messenger Rna ◽

Tuberculosis Treatment ◽

Rna Expression

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Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

mBio ◽

10.1128/mbio.03293-19 ◽

2020 ◽

Vol 11 (2) ◽

Cited By ~ 6

Author(s):

Priyanka Tyagi ◽

Virender Kumar Pal ◽

Ragini Agrawal ◽

Shalini Singh ◽

Sandhya Srinivasan ◽

...

Keyword(s):

Oxidative Stress ◽

Mycobacterium Tuberculosis ◽

Clinical Findings ◽

Host Factors ◽

Human Pathogens ◽

Content Type ◽

Respiratory Parameters ◽

Consumption Rates ◽

The One ◽

Hiv 1

ABSTRACT The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant—N-acetyl cysteine (NAC)—or with inhibitors of host factors—galectins and Hsp90—attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies. IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.

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Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis

Science Translational Medicine ◽

10.1126/scitranslmed.aaw6635 ◽

2019 ◽

Vol 11 (518) ◽

pp. eaaw6635 ◽

Cited By ~ 16

Author(s):

Richa Mishra ◽

Sakshi Kohli ◽

Nitish Malhotra ◽

Parijat Bandyopadhyay ◽

Mansi Mehta ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Tolerance ◽

Antibiotic Tolerance ◽

Lung Pathology ◽

In Vivo Models ◽

Drug Efflux Pumps ◽

Major Drug ◽

Hiv 1 ◽

Multiple Antibiotics

The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (Cmax and AUClast) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.

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A19 The impact of HIV-1 on the evolution of Mycobacterium tuberculosis

Virus Evolution ◽

10.1093/ve/vey010.018 ◽

2018 ◽

Vol 4 (suppl_1) ◽

Author(s):

Anastasia Koch ◽

Daniela Brites ◽

David Stucki ◽

Joanna C Evans ◽

Ronnett Seldon ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

The Impact ◽

Hiv 1

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Preferential infection and depletion of Mycobacterium tuberculosis–specific CD4 T cells after HIV-1 infection

Journal of Experimental Medicine ◽

10.1084/jem.20100090 ◽

2010 ◽

Vol 207 (13) ◽

pp. 2869-2881 ◽

Cited By ~ 155

Author(s):

Christof Geldmacher ◽

Njabulo Ngwenyama ◽

Alexandra Schuetz ◽

Constantinos Petrovas ◽

Klaus Reither ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Hiv Infection ◽

Cd4 T Cells ◽

Staphylococcal Enterotoxin B ◽

Opportunistic Pathogens ◽

Rapid Loss ◽

Hiv 1

HIV-1 infection results in the progressive loss of CD4 T cells. In this study, we address how different pathogen-specific CD4 T cells are affected by HIV infection and the cellular parameters involved. We found striking differences in the depletion rates between CD4 T cells to two common opportunistic pathogens, cytomegalovirus (CMV) and Mycobacterium tuberculosis (MTB). CMV-specific CD4 T cells persisted after HIV infection, whereas MTB-specific CD4 T cells were depleted rapidly. CMV-specific CD4 T cells expressed a mature phenotype and produced very little IL-2, but large amounts of MIP-1β. In contrast, MTB-specific CD4 T cells were less mature, and most produced IL-2 but not MIP-1β. Staphylococcal enterotoxin B–stimulated IL-2–producing cells were more susceptible to HIV infection in vitro than MIP-1β–producing cells. Moreover, IL-2 production was associated with expression of CD25, and neutralization of IL-2 completely abrogated productive HIV infection in vitro. HIV DNA was found to be most abundant in IL-2–producing cells, and least abundant in MIP-1β–producing MTB-specific CD4 T cells from HIV-infected subjects with active tuberculosis. These data support the hypothesis that differences in function affect the susceptibility of pathogen-specific CD4 T cells to HIV infection and depletion in vivo, providing a potential mechanism to explain the rapid loss of MTB-specific CD4 T cells after HIV infection.

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