Imaging lymphoid tissues in nonhuman primates to understand SIV pathogenesis and persistence

Deléage, Claire; Türkbey, Barış; Estes, Jacob D.

doi:10.1016/j.coviro.2016.07.002

Cited by 19 publications

(17 citation statements)

References 53 publications

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“…RNAscope and immunostaining. For the detection of HIV RNA-positive cells in skin biopsies, RNAscope in situ hybridization was performed as previously reported (28). Immunohistochemical analysis was performed to determine histopathologic changes and the tissue immune cell composition of CD4 + and CD8 + T cells and CD68 + CD163 + macrophages (Supplemental Methods).…”

Section: Methodsmentioning

confidence: 99%

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate

Jiang¹,

Maverakis²,

Cheng³

et al. 2019

JCI Insight

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Section: Methodsmentioning

confidence: 99%

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate

Jiang¹,

Maverakis²,

Cheng³

et al. 2019

JCI Insight

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“…During antiretroviral therapy (ART), the frequency of HIV RNA + cells in LNs and B-cell follicles is reduced and lymphoid architecture is at least partially restored ( 6 ). However, RNA + cells are still detected in B-cell follicles during ART in both HIV and SIV infection ( 7 – 9 ). It remains controversial whether HIV RNA + cells found in SLOs during ART are the result of successful new infection or reactivation of latently infected cells.…”

Section: The B-cell Follicle In Untreated and Treated Diseasementioning

confidence: 99%

The B-Cell Follicle in HIV Infection: Barrier to a Cure

2018

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The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA + cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA + cells in the B-cell follicle is mediated by several factors. Follicular CD4 + T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets. The B cell follicle also contains a large reservoir of extracellular HIV virions, which accumulate on the surface of follicular dendritic cells (FDCs) in germinal centers. FDC-bound HIV virions remain infectious even in the presence of neutralizing antibodies and can persist for months or even years. Moreover, the B-cell follicle is semi-immune privileged from CTL control. Frequencies of HIV- and SIV-specific CTL are lower in B-cell follicles compared to extrafollicular regions as the majority of CTL do not express the follicular homing receptor CXCR5. Additionally, CTL in the B-cell follicle may be less functional than extrafollicular CTL as many exhibit the recently described CD8 T follicular regulatory phenotype. Other factors may also contribute to the follicular concentration of HIV RNA + cells. Notably, the contribution of NK cells and γδ T cells to control and/or persistence of HIV RNA + cells in secondary lymphoid tissue remains poorly characterized. As HIV research moves increasingly toward the development of cure strategies, a greater understanding of the barriers to control of HIV infection in B-cell follicles is critical. Although no strategy has as of yet proven to be effective, a range of novel therapies to address these barriers are currently being investigated including genetically engineered CTL or chimeric antigen receptor T cells that express the follicular homing molecule CXCR5, treatment with IL-15 or an IL-15 superagonist, use of bispecific antibodies to harness the killing power of the follicular CD8 + T cell population, and disruption of the follicle through treatments such as rituximab.

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“…While HLACs allow for more cellular analysis of viability and infection via flow cytometry, the human tonsil explant tissue block model allows for preservation of the tonsil tissue cytoarchitecture. Given prior evidence that a lymphoid tissue microenvironment can support the course of HIV-1 infection and pyroptosis in both HLACs and tissue blocks (51,54,56,(58)(59)(60), we pursued the development of a tonsil model that could recapitulate the observations of HIV-1 infection and stimulation of inflammatory cytokine production. To do this, tonsils were dissected and cut into small blocks and suspended at the liquid-air interface on collagen rafts.…”

mentioning

confidence: 99%

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

Soare

Durham

Gopal

et al. 2019

J Virol

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HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. Anex vivohuman tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCEPatients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

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Imaging lymphoid tissues in nonhuman primates to understand SIV pathogenesis and persistence

Cited by 19 publications

References 53 publications

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate

The B-Cell Follicle in HIV Infection: Barrier to a Cure

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

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