Vaccine strategies for the Mtb/HIV copandemic

Sharan, Riti; Kaushal, Deepak

doi:10.1038/s41541-020-00245-9

Cited by 10 publications

(8 citation statements)

References 102 publications

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“…Thus, it is important to understand the driving forces behind chronic immune activation in a relevant coinfected preclinical model. This will lead to the discovery of key biomarkers predicting LTBI reactivation and therefore point the way to intervention strategies ( 13 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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

Sharan¹,

Ganatra²,

Bucşan³

et al. 2022

Journal of Clinical Investigation

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Studies using the nonhuman primate model of M. tuberculosis /Simian Immunodeficiency Virus co-infection have revealed protective CD4 + T cell-independent immune responses that suppress LTBI reactivation. In particular, chronic immune activation rather than the mere depletion of CD4 + T cells correlates with reactivation due to SIV co-infection. Here, we administered cART at 2 weeks post-SIV co-infection to study if restoration of CD4 + T cell immunity occurred more broadly, and if this prevented reactivation of LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication and reduced immune activation in the periphery and lung vasculature thereby reducing the rate of SIVinduced reactivation. We observed robust CD8 + T effector memory responses and significantly reduced macrophage turnover in the lung tissue. However, skewed CD4 + T effector memory responses persisted and new TB lesions formed post SIV co-infection. Thus, reactivation of LTBI is governed by very early events of SIV infection. Timing of cART is critical in mitigating chronic immune activation. The novelty of these findings mainly relates to the development of a robust animal model of human Mtb/HIV co-infection that allows the testing of underlying mechanisms.

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Section: Introductionmentioning

confidence: 99%

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

Sharan¹,

Ganatra²,

Bucşan³

et al. 2022

Journal of Clinical Investigation

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“…The risk of TB is increased in PLWH, even before CD4 + T cell counts decline significantly ( 74 ). Furthermore, active vaccination with BCG is contraindicated in PLWH due to the risk of dissemination ( 75 , 76 ), and combining antiretroviral regiments with TB chemotherapy can be challenging due to potential drug-drug interaction ( 77 ). Given the challenges of current treatment regimens and the lack of an effective prophylactic vaccine, exploring alternatives for TB control is crucial ( 78 ).…”

Section: Discussionmentioning

confidence: 99%

An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis

Paterson,

La Manna,

Arena De Souza

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.

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“…The HIV-1 HIVA immunogen, designed by Dr. Tomas Hanke, is composed of the full-length HIV-1 Gag protein combined with multiple CTL epitopes including P18I10 epitopes at the C-terminus [ 34 ]. The DNA, MVA and rBCG were selected as HIVA immunogen delivery vehicles and induced high magnitude and breadth of CTL epitope-specific cellular responses by using heterologous prime-boost regimes in mouse and non-human primate (NHP) models [ 34 , 101 ]. Our prior studies have shown that rBCG.HIVA prime in combination with MVA.HIVA boost elicited HIV-1-specific IFN-γ producing CD8+ T-cells in BALB/c mice [ 31 , 32 , 33 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

Chimeric Human Papillomavirus-16 Virus-like Particles Presenting P18I10 and T20 Peptides from HIV-1 Envelope Induce HPV16 and HIV-1-Specific Humoral and T Cell-Mediated Immunity in BALB/c Mice

et al. 2022

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In this study, the HIV-1 P18I10 CTL peptide derived from the V3 loop of HIV-1 gp120 and the T20 anti-fusion peptide of HIV-1 gp41 were inserted into the HPV16 L1 capsid protein to construct chimeric HPV:HIV (L1:P18I10 and L1:T20) VLPs by using the mammalian cell expression system. The HPV:HIV VLPs were purified by chromatography. We demonstrated that the insertion of P18I10 or T20 peptides into the DE loop of HPV16 L1 capsid proteins did not affect in vitro stability, self-assembly and morphology of chimeric HPV:HIV VLPs. Importantly, it did not interfere either with the HIV-1 antibody reactivity targeting sequential and conformational P18I10 and T20 peptides presented on chimeric HPV:HIV VLPs or with the induction of HPV16 L1-specific antibodies in vivo. We observed that chimeric L1:P18I10/L1:T20 VLPs vaccines could induce HPV16- but weak HIV-1-specific antibody responses and elicited HPV16- and HIV-1-specific T-cell responses in BALB/c mice. Moreover, could be a potential booster to increase HIV-specific cellular responses in the heterologous immunization after priming with rBCG.HIVA vaccine. This research work would contribute a step towards the development of the novel chimeric HPV:HIV VLP-based vaccine platform for controlling HPV16 and HIV-1 infection, which is urgently needed in developing and industrialized countries.

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Vaccine strategies for the Mtb/HIV copandemic

Cited by 10 publications

References 102 publications

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

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

An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis

Chimeric Human Papillomavirus-16 Virus-like Particles Presenting P18I10 and T20 Peptides from HIV-1 Envelope Induce HPV16 and HIV-1-Specific Humoral and T Cell-Mediated Immunity in BALB/c Mice

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