Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis

Schacker, Timothy W.; Nguyen, Phuong L.; Beilman, Greg J.; Wolinsky, Steven M.; Larson, Matthew; Reilly, Cavan; Haase, Ashley T.

doi:10.1172/jci200216413

Cited by 43 publications

(34 citation statements)

References 20 publications

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“…We initially compared subject WU59 with GL38 because of their divergent PLOD2 mRNA expression (Figure 5A) and found a relationship between PLOD2 mRNA expression and collagen type I deposition, whereby greater levels of fibrosis were detected in the lymph node of subject GL38 coincident with higher levels of PLOD2 mRNA (compare Figures 5B & 5C). Previously reported to be increased during HIV-1 infection (15), much less collagen deposition was seen in the lymph node of an uninfected individual (Figure 5D). There was also a negative correlation between collagen deposition in LT and numbers of peripheral blood CD4 + T cells in a group of our study subjects (Figure 5E), in agreement with previous reports (15, 16), suggesting that increased fibrosis during HIV-1 infection may negatively impact viral replication by adversely affecting CD4 + T cell viability and reducing access to and availability of target cells for viral replication.…”

Section: Resultssupporting

confidence: 47%

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Host Genes Associated with HIV-1 Replication in Lymphatic Tissue

Smith

Wietgrefe

et al. 2010

The Journal of Immunology

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Much effort has been spent recently in identifying host factors required for HIV-1 to effectively replicate in cultured human cells. However, much less is known about the genetic factors in vivo that impact viral replication in lymphatic tissue, the primary anatomical site of virus–host interactions where the bulk of viral replication and pathogenesis occurs. To identify genetic determinants in lymphatic tissue that critically affect HIV-1 replication, we used microarrays to transcriptionally profile and identify host genes expressed in inguinal lymph nodes that were associated determinants of viral load. Strikingly, ∼95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset 1) inhibit cellular activation/proliferation (e.g., TCFL5, SOCS5 and SCOS7, KLF10), 2) promote heterochromatin formation (e.g., HIC2, CREBZF, ZNF148/ZBP-89), 3) increase collagen synthesis (e.g., PLOD2, POSTN, CRTAP), and 4) reduce cellular transcription and translation. Potential anti–HIV-1 restriction factors were also identified (e.g., NR3C1, HNRNPU, PACT). Only ∼5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all of these genes function in innate and adaptive immunity, particularly highlighting heightened gene expression in the IFN system. We conclude that this conventional host response cannot contain HIV-1 replication and, in fact, could well contribute to increased replication through immune activation. More importantly, genes that have a negative association with virus replication point to target cell availability and potentially new viral restriction factors as principal determinants of viral load.

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Section: Resultssupporting

confidence: 47%

“…Collagen deposition in this model negatively impacts viral load through fibrotic damage of the lymph node niche and its documented effects of decreasing CD4 + T cells (Figure 5E) (15, 16), essentially decreasing access and opportunities for virus to interact with target cells.…”

Section: Discussionmentioning

confidence: 99%

Host Genes Associated with HIV-1 Replication in Lymphatic Tissue

Smith

Wietgrefe

et al. 2010

The Journal of Immunology

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“…Thymic and T-cell progenitor dysfunction, most likely caused by aberrantly high levels of pro-inflammatory cytokines expressed during untreated HIV infection, have been reported (43, 131) and the loss of such progenitor cells could aggravate the depleting effects of chronic immune activation on the adaptive immune system. Moreover, continuous inflammation in lymph nodes has been suggested to result in TGFβ-induced collagen deposition, fibrosis, and pathological changes in lymph node architecture, possibly adding to impaired T-cell proliferation and survival (132–134). Continuous activation has recently been shown to induce upregulation of inhibitory receptors such as programed death-1 (PD-1), CTLA-4, and Tim-3, which may interfere with ongoing HIV-specific T-cell responses, and ultimately lead to T-cell anergy and loss of HIV-specific T cells (135–137).…”

Section: Pathogenic Effects Of Immune Activation and Inflammationmentioning

confidence: 99%

Immune Activation and Collateral Damage in AIDS Pathogenesis

Miedema¹,

Hazenberg²,

Tesselaar³

et al. 2013

Front. Immunol.

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In the past decade, evidence has accumulated that human immunodeficiency virus (HIV)-induced chronic immune activation drives progression to AIDS. Studies among different monkey species have shown that the difference between pathological and non-pathological infection is determined by the response of the immune system to the virus, rather than its cytopathicity. Here we review the current understanding of the various mechanisms driving chronic immune activation in HIV infection, the cell types involved, its effects on HIV-specific immunity, and how persistent inflammation may cause AIDS and the wide spectrum of non-AIDS related pathology. We argue that therapeutic relief of inflammation may be beneficial to delay HIV-disease progression and to reduce non-AIDS related pathological side effects of HIV-induced chronic immune stimulation.

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“…Studies of HIV-infected individuals suggested cross-talk between microbial translocation, the activation of monocytes, CD4 + T cells and CD8 + T cells, and the depletion of CD4 + T cells. In the setting of chronic HIV infection, TGF-b1 secretion in response to LPS drives deposition of collagen in the T cell zones of lymphatic tissues, where naïve CD4 + T cells undergo homeostatic proliferation due to IL-7 and exposure to antigen presented by dendritic cells 21 .…”

Section: Mechanisms Of Microbial Translocationmentioning

confidence: 99%