Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a Mycobacterium tuberculosis/SIV coinfection model

Sharan, Riti; Ganatra, Shashank; Bucşan, Allison N.; Cole, Journey; Singh, Dhiraj Kumar; Álvarez, Xavier; Gough, Maya; Alvarez, Cynthia; Blakley, Alyssa; Ferdin, Justin; Thippeshappa, Rajesh; Singh, Bindu; Escobedo, Ruby; Shivanna, Vinay; Dick, Edward J.; Hall-Ursone, Shannan; Khader, Shabaana A.; Mehra, Smriti; Rengarajan, Jyothi; Kaushal, Deepak

doi:10.1172/jci153090

Cited by 9 publications

(27 citation statements)

References 59 publications

(114 reference statements)

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“…In conjunction, K/T ratios have been shown to cause increased T regulatory cells and decreased T effector memory cells which may impair host response during active infection [ 52 ]. More recently, we have shown in the NHP model of Mtb /SIV co-infection, that myeloid cell turnover is directly correlated with uncontrolled immune activation and reactivation of TB [ 28 , 53 , 54 ]. A recent multiplexed imaging study also indicates that expression of IDO on myeloid cells is a key feature of human TB granulomas [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques

et al. 2022

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Despite a century of research into tuberculosis (TB), there is a dearth of reproducible, easily quantifiable, biomarkers that can predict disease onset and differentiate between host disease states. Due to the challenges associated with human sampling, nonhuman primates (NHPs) are utilized for recapitulating the closest possible modelling of human TB. To establish a predictive peripheral biomarker profile based on a larger cohort of rhesus macaques (RM), we analyzed results pertaining to peripheral blood serum chemistry and cell counts from RMs that were experimentally exposed to Mtb in our prior studies and characterized as having either developed active TB (ATB) disease or latent TB infection (LTBI). We compared lung CFU burdens and quantitative pathologies with a number of measurables in the peripheral blood. Based on our results, the investigations were then extended to the study of specific molecules and cells in the lung compartments of a subset of these animals and their immune responses. In addition to the elevated serum C-reactive protein (CRP) levels, frequently used to discern the level of Mtb infection in model systems, reduced serum albumin-to-globulin (A/G) ratios were also predictive of active TB disease. Furthermore, higher peripheral myeloid cell levels, particularly those of neutrophils, kynurenine-to-tryptophan ratio, an indicator of induced expression of the immunosuppressive molecule indoleamine dioxygenase, and an influx of myeloid cell populations could also efficiently discriminate between ATB and LTBI in experimentally infected macaques. These quantifiable correlates of disease were then used in conjunction with a regression-based analysis to predict bacterial load. Our results suggest a potential biomarker profile of TB disease in rhesus macaques, that could inform future NHP–TB research. Our results thus suggest that specific biomarkers may be developed from the myeloid subset of peripheral blood or plasma with the ability to discriminate between active and latent Mtb infection.

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Section: Discussionmentioning

confidence: 99%

Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques

et al. 2022

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“…Animals were chosen if they were experimentally infected with 10-25 Colony Forming Units (CFU) of Mtb (CDC1551 strain) or co-infected with Mtb (CDC1551)/SIV (SIVmac239) during 2011-2014 but were not treated with any antibiotics. Co-infection with SIV was always performed at 9 weeks post- Mtb infection, and with 300 TCID50 virus using the intravenous route, as described in our previous publications ( 1 , 16 – 18 , 20 , 21 ). CD4 depletion in blood and BAL along with plasma viral load was used to confirm productive SIV infection.…”

Section: Methodsmentioning

confidence: 99%

“…Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), is the most prevalent opportunistic disease in human immunodeficiency virus ( 1 )-infected individuals globally. Worldwide, TB coinfection accounts for >30% of total HIV associated deaths ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, experiments in this model suggest that the mere depletion of CD4 + T cells is not sufficient to cause reactivation ( 18 ). We have postulated that chronic immune activation due to SIV ( 1 ) co-infection, mediates macrophage turnover and immune dysfunction, resulting in reactivation ( 19 ). Consistent with this, initiation of highly active anti-retroviral therapy (HAART) at a time when signs of macrophage turnover are apparent fails to protect Mtb /SIV co-infected RM from reactivation, despite impressive control of viral replication and reconstitution of CD4+ T cells ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with this, initiation of highly active anti-retroviral therapy (HAART) at a time when signs of macrophage turnover are apparent fails to protect Mtb /SIV co-infected RM from reactivation, despite impressive control of viral replication and reconstitution of CD4+ T cells ( 20 ). Initiation of ART at earlier time-points is more beneficial, further suggesting that macrophage turnover is the critical determinant of lung-specific chronic immune activation during Mtb /SIV co-infection which causes reactivation ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

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System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb/SIV co-infection

Gough

Singh²,

Singh³

et al. 2022

Front. Immunol.

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Mycobacterium tuberculosis (Mtb) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. Mtb infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with Mtb and Simian Immunodeficiency Virus (Mtb/SIV), we are able to simulate human progression of TB/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Identifying correlates of immune control of infection is important for both vaccine and therapeutics development. Using macaques infected with Mtb or Mtb/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators). We particularly focused on pathways relevant to myeloid origin cells such as macrophages, as these innate immunocytes have an important contribution to the initial control or the lack thereof, following Mtb infection. Using bacterial burden, C-reactive protein (CRP), and other clinical indicators of disease severity as a guide, we were able to establish gene signatures of host disease state and progression. In addition to gene signatures, clustering algorithms were used to differentiate between host disease states and identify relationships between genes. This allowed us to identify clusters of genes which exhibited differential expression profiles between the three groups of macaques: ATB, LTBI and Mtb/SIV. The gene signatures were associated with pathways relevant to apoptosis, ATP production, phagocytosis, cell migration, and Type I interferon (IFN), which are related to macrophage function. Our results suggest novel macrophage functions that may play roles in the control of Mtb infection with and without co-infection with SIV. These results particularly point towards an interplay between Type I IFN signaling and IFN-γ signaling, and the resulting impact on lung macrophages as an important determinant of progression to TB.

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Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques

Larson

Ellis²,

Rodgers

et al. 2022

Preprint

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Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naïve and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis(Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4-8 year-old children were intravenously infected with SIVmac239M, treated with ART three months later, and coinfected with Mtb three months after initiating ART. SIV-naïve macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naïve macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naïve macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas obtained at necropsy, nor did they differ in the frequency of immune checkpoint and proliferative markers. Thus, ART treatment of juvenile macaques, three months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naïve macaques.

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Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a Mycobacterium tuberculosis/SIV coinfection model

Cited by 9 publications

References 59 publications

Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques

Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques

System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb/SIV co-infection

Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques

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