Effect of HIV on the Frequency and Number of Mycobacterium tuberculosis–Specific CD4+ T Cells in Blood and Airways During Latent M. tuberculosis Infection

Bunjun, Rubina; Riou, Catherine; Soares, Andreia; Thawer, Narjis; Müller, Tracey L.; Kiravu, Agano; Ginbot, Zekarias; Oni, Tolu; Goliath, René; Kalsdorf, Barbara; Groote-Bidlingmaier, Florian von; Hanekom, Willem A.; Walzl, Gerhard; Wilkinson, Robert J.; Burgers, Wendy A.

doi:10.1093/infdis/jix529

Cited by 25 publications

(27 citation statements)

References 39 publications

(45 reference statements)

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“…This latter phenomenon has also been observed during Mtb/SIV infection in macaques [48]. It is important to understand how HIV directly affects granulomas as responses in PBMC, BAL, and granulomas are not well correlated, as observed in this study and others [11,12,14,15,43].…”

Section: Discussionsupporting

confidence: 58%

“…We did not find overt PBMC immune responses that correlated with reactivation in either the Mtb/αCD4 or Mtb/SIV groups. HIV/Mtb co-infection clinical studies have demonstrated that HIV preferentially induces an overall reduction in Mtb-specific PBMC production of IL-2 producing PLOS PATHOGENS peripheral CD4 T cells [41], Mtb-specific IL-17 and Th1 producing cytokines from T cells [42][43][44][45], and Th transcription factors (e.g., FoxP3, T-bet) within Mtb-specific CD4 T cells [46]. In one study, 5 patients with newly acquired HIV infection and LTBI were found to have reduced frequencies of Mtb-specific CD4 T cells though none developed reactivation in the first year of seroconversion [41].…”

Section: Discussionmentioning

confidence: 99%

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SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

et al. 2020

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Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/ or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

et al. 2020

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“…Progressive depletion and dysfunction of CD4 T-cells following HIV infection leads to immune suppression and negatively impacts immunity to M. tuberculosis . Specific depletion of M. tuberculosis -specific CD4 T-cells has been reported in the peripheral blood(15, 16) and broncheoalveolar lavage (BAL) samples(17, 18) of HIV-infected individuals with LTBI. Several studies indicate that specific depletion may be a consequence of enhanced HIV co-receptor expression in CD4 T-cells, particularly CCR5, in TB patients(15, 19–24).…”

Section: Immunopathogenesis Of Tuberculosis In Humans and Animal Modelsmentioning

confidence: 99%

Immunology ofMycobacterium tuberculosisInfections

2019

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Tuberculosis (TB) is a serious global public health challenge that results in significant morbidity and mortality worldwide. TB is caused by infection with the bacilli Mycobacterium tuberculosis ( M. tuberculosis ), which has evolved a wide variety of strategies in order to thrive within its host. Understanding the complex interactions between M. tuberculosis and host immunity can inform the rational design of better TB vaccines and therapeutics. This chapter covers innate and adaptive immunity against M. tuberculosis infection, including insights on bacterial immune evasion and subversion garnered from animal models of infection and human studies. In addition, this chapter discusses the immunology of the TB granuloma, TB diagnostics, and TB comorbidities. Finally, this chapter provides a broad overview of the current TB vaccine pipeline.

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“…It has recently been shown that the activation profile of Mtb-specific CD4 + T cells as assessed by the expression of CD38, HLA-DR, and Ki-67 reflects TB disease in both HIV infected and uninfected individuals ( 24 ). It is interesting to speculate that expression of caspase-3 in Mtb-specific CD4 + T cells from HIV-infected ATB patients will be similarly higher compared to HIV infected individuals with LTBI despite the reduction of peripheral CD4 + T cells during HIV infection ( 25 , 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

High Frequencies of Caspase-3 Expressing Mycobacterium tuberculosis-Specific CD4+ T Cells Are Associated With Active Tuberculosis

et al. 2018

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Antigen-specific CD4+ T cell responses to Mycobacterium tuberculosis (Mtb) infection are important for host defense against tuberculosis (TB). However, Mtb-specific IFN-γ-producing T cells do not distinguish active tuberculosis (ATB) patients from individuals with asymptomatic latent Mtb infection (LTBI). We reasoned that the immune phenotype of Mtb-specific IFN-γ+CD4+ T cells could provide an indirect gauge of Mtb antigen load within individuals. We sought to identify immune markers in Mtb-specific IFN-γ+CD4+ T cells and hypothesized that expression of caspase-3 Mtb-specific CD4+ T cells would be associated with ATB. Using polychromatic flow cytometry, we evaluated the expression of caspase-3 in Mtb-specific CD4+ T cells from LTBI and ATB as well as from ATB patients undergoing anti-TB treatment. We found significantly higher frequencies of Mtb-specific caspase-3+IFN-γ+CD4+ T cells in ATB compared to LTBI. Caspase-3+IFN-γ+CD4+ T cells were also more activated compared to their caspase-3-negative counterparts. Furthermore, the frequencies of caspase-3+IFN-γ+CD4+ T cells decreased in response to anti-TB treatment. Our studies suggest that the frequencies of caspase-3-expressing antigen-specific CD4+ T cells may reflect mycobacterial burden in vivo and may be useful for distinguishing Mtb infection status along with other host biomarkers.

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Effect of HIV on the Frequency and Number of Mycobacterium tuberculosis–Specific CD4+ T Cells in Blood and Airways During Latent M. tuberculosis Infection

Abstract: Human immunodeficiency virus infection leads to lower frequencies of CD4+ T cells specific for Mycobacterium tuberculosis in blood and lungs. However, an influx of T cells to the lungs results in similar absolute numbers of specific CD4+ T cells, compared with uninfected individuals.

Cited by 25 publications

References 39 publications

SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

Immunology ofMycobacterium tuberculosisInfections

High Frequencies of Caspase-3 Expressing Mycobacterium tuberculosis-Specific CD4+ T Cells Are Associated With Active Tuberculosis

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