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The Immune Interaction between HIV-1 Infection and

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  • Authors: Elsa Du Bruyn1, Robert John Wilkinson2,3
  • Editors: William R. Jacobs Jr.4, Helen McShane5, Valerie Mizrahi6, Ian M. Orme7
    Affiliations: 1: Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa; 2: Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa; 3: Department of Medicine, Imperial College London, London W2 1PG and The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, United Kingdom; 4: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 5: University of Oxford, Oxford OX3 7DQ, United Kingdom; 6: University of Cape Town, Rondebosch 7701, South Africa; 7: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0012-2016
  • Received 31 January 2016 Accepted 13 February 2016 Published 16 December 2016
  • E. du Bruyn, [email protected]
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  • Abstract:

    The modulation of tuberculosis (TB)-induced immunopathology caused by human immunodeficiency virus (HIV)-1 coinfection remains incompletely understood but underlies the change seen in the natural history, presentation, and prognosis of TB in such patients. The deleterious combination of these two pathogens has been dubbed a “deadly syndemic,” with each favoring the replication of the other and thereby contributing to accelerated disease morbidity and mortality. HIV-1 is the best-recognized risk factor for the development of active TB and accounts for 13% of cases globally. The advent of combination antiretroviral therapy (ART) has considerably mitigated this risk. Rapid roll-out of ART globally and the recent recommendation by the World Health Organization (WHO) to initiate ART for everyone living with HIV at any CD4 cell count should lead to further reductions in HIV-1-associated TB incidence because susceptibility to TB is inversely proportional to CD4 count. However, it is important to note that even after successful ART, patients with HIV-1 are still at increased risk for TB. Indeed, in settings of high TB incidence, the occurrence of TB often remains the first presentation of, and thereby the entry into, HIV care. As advantageous as ART-induced immune recovery is, it may also give rise to immunopathology, especially in the lower-CD4-count strata in the form of the immune reconstitution inflammatory syndrome. TB-immune reconstitution inflammatory syndrome will continue to impact the HIV-TB syndemic.

  • Citation: Du Bruyn E, Wilkinson R. 2016. The Immune Interaction between HIV-1 Infection and . Microbiol Spectrum 4(6):TBTB2-0012-2016. doi:10.1128/microbiolspec.TBTB2-0012-2016.


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The modulation of tuberculosis (TB)-induced immunopathology caused by human immunodeficiency virus (HIV)-1 coinfection remains incompletely understood but underlies the change seen in the natural history, presentation, and prognosis of TB in such patients. The deleterious combination of these two pathogens has been dubbed a “deadly syndemic,” with each favoring the replication of the other and thereby contributing to accelerated disease morbidity and mortality. HIV-1 is the best-recognized risk factor for the development of active TB and accounts for 13% of cases globally. The advent of combination antiretroviral therapy (ART) has considerably mitigated this risk. Rapid roll-out of ART globally and the recent recommendation by the World Health Organization (WHO) to initiate ART for everyone living with HIV at any CD4 cell count should lead to further reductions in HIV-1-associated TB incidence because susceptibility to TB is inversely proportional to CD4 count. However, it is important to note that even after successful ART, patients with HIV-1 are still at increased risk for TB. Indeed, in settings of high TB incidence, the occurrence of TB often remains the first presentation of, and thereby the entry into, HIV care. As advantageous as ART-induced immune recovery is, it may also give rise to immunopathology, especially in the lower-CD4-count strata in the form of the immune reconstitution inflammatory syndrome. TB-immune reconstitution inflammatory syndrome will continue to impact the HIV-TB syndemic.

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Spectrum of disease in HIV-TB coinfection. The axis represents stages of tuberculosis, from infection through to active disease, while the axis represents stages of HIV-1 infection. bacterial burden and CD4 count are shown in blue along the respective axes. The spectrum of latent TB is represented as follows: infection eliminated without priming antigen-specific T cells; infection eliminated in association with T-cell priming; infection contained with some bacteria persisting in a nonreplicating form; bacterial replication maintained at the subclinical level by the immune system. Clinical disease (pulmonary and extrapulmonary tuberculosis) occurs in a subset of individuals who are latently infected or who develop primary tuberculosis directly following infection or reinfection. The annual risk is represented as follows: HIV-1-uninfected: about 10% lifetime risk or about 1% per annum (p/a); shortly after HIV-1 infection and prior to substantial CD4 T-cell depletion, the risk of active tuberculosis increases; during the early stages of HIV-1 infection, this risk rises to approximately 10% p/a; in late-stage HIV-1 infection, the risk of active tuberculosis increases to 30% p/a. The effects of HIV-1 on tuberculosis and of tuberculosis on HIV-1 disease are shown by the red arrows. Reproduced from ( 286 ) with permission of the publisher.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0012-2016
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A model of innate receptor signaling in mediating TB-IRIS pathogenesis as proposed by Lai et al. Microarray profiling revealed that TLR signaling and inflammasome activation are critical in mediating TB-IRIS pathogenesis. The proposed model begins with antigen recognition by surface-expressing TLRs, which triggers the downstream signaling cascade with adaptor molecules such as MyD88 and IRAK4 to activate IRF7, thereby triggering the production of type I IFN. Paracrine signaling of type I IFN to IFNAR recruits and phosphorylates STAT1/2 dimers, leading to further recruitment of IRF9 and the formation of ISGF3, thereby inducing pro-caspase-11 (caspase-4/5 in human) and AIM-2 inflammasome (caspase-1). Caspase-11 cleaves IL-1α into its mature form and can lead to pyroptosis. The noncanonical inflammasome (caspase-11) can also activate the canonical inflammasome (caspase-1), which cleaves IL-1β and IL-18 into their mature form. Alternatively, TLR signaling via MyD88 can also activate NF-κB via the TAK1/IKK complex. Activation of NF-κB triggers the production of an array of cytokines, including TNF-α, IL-6, and IL-12. In addition, NF-κB also activates NLRP1/3 inflammasomes and subsequently leads to the production of IL-1β and IL-18. Reproduced from ( 287 ) with permission of the publisher.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0012-2016
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-derived PAMPs and cytokines mediating enhanced HIV-1 replication : PAMP-mediated activation of HIV-LTR

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0012-2016
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-derived cytokines mediating enhanced HIV-1 replication: cytokines produced in response activating HIV-1 LTR

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0012-2016
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T lymphocyte dysfunction in the setting of HIV-TB coinfection and the effect of ART

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0012-2016

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