Mucosal stromal fibroblasts markedly enhance HIV infection of CD4+ T cells

Neidleman, Jason; Chen, Joseph C.; Kohgadai, Nargis; Müller, Janis A.; Laustsen, Anders; Thavachelvam, Karthiga; Jang, Karen; Stürzel, Christina M.; Jones, Jennifer; Ochsenbauer, Christina; Chitre, Avantika S.; Somsouk, Ma; Garcia, Maurice M.; Smith, James F.; Greenblatt, Ruth M.; Münch, Jan; Jakobsen, Martin R.; Giudice, Linda C.; Greene, Warner C.; Roan, Nadia R.

doi:10.1371/journal.ppat.1006163

Cited by 54 publications

(64 citation statements)

References 70 publications

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“…Previous studies have shown that fibroblasts can enhance HIV infection of CD4+ T cells in a contact-dependent manner. 59 Together with our study, this suggests distinct contact-independent and de-…”

Section: Ta B L E 1 Constitutive Cytokine Secretion By Frt Stromal Fisupporting

confidence: 84%

“…One explanation for this finding is that E 2 upregulates SDF-1α, which is known to competitively inhibit viral binding to the CXCR4 co-receptor 58 , and thus reduce viral entry into the cell. Previous studies have shown that fibroblasts can enhance HIV infection of CD4+ T cells in a contact-dependent manner 59 . Together with our study, this suggests distinct contact-independent and dependent contributions by fibroblasts to HIV susceptibility of CD4+ T cells.…”

Section: Discussionmentioning

confidence: 99%

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Estradiol‐regulated innate antiviral responses of human endometrial stromal fibroblasts

Patel

Shen

Rossoll

et al. 2018

American J Rep Immunol

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Problem: The contribution of fibroblasts to innate immune protection of the human female reproductive tract (FRT) against viral pathogens is relatively unknown. Method of Study: Endometrial (EM), endocervical (Cx), and ectocervical (ECx) fibroblasts were isolated from hysterectomy patients and grown in vitro. Fibroblasts were treated with the viral mimic poly (I:C) in the presence or absence of the sex hormone estradiol (E2), with gene expression measured by real-time RT-PCR and protein secretion by ELISA. Results: Poly (I:C) induced the expression of the interferon-stimulated genes (ISG) MxA, OAS2 and APOBEC3G, and the cytokines MCP-1, IL-8, IL-6, CCL20, IFNβ and RANTES by fibroblasts from all three sites. ISG upregulation was dependent upon Type I IFN signaling. E2 inhibited the poly (I:C)-induced upregulation of MxA and OAS2 in EM fibroblasts, but not Cx or ECx fibroblasts. E2 upregulated SDF-1α by EM fibroblasts but had no effect on secretion of other cytokines either alone or in the presence of poly (I:C). Conditioned media (CM) from poly (I:C)-treated or E2-treated fibroblasts significantly reduced HIV infection of CD4+ T cells. Conclusions: Stromal fibroblasts represent a level of innate immune protection against viral pathogens in the FRT beyond that seen with epithelial cells and immune cells. Our findings indicate that fibroblasts FRT are selectively responsive to E2, capable of initiating an antiviral response against viral pathogens, and may play a role in preventing HIV infection of CD4+ T cells.

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Section: Ta B L E 1 Constitutive Cytokine Secretion By Frt Stromal Fisupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Estradiol‐regulated innate antiviral responses of human endometrial stromal fibroblasts

Patel

Shen

Rossoll

et al. 2018

American J Rep Immunol

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“…Male‐to‐female HIV transmission rates approximate 0.12% per sex act , implying the virus must overcome host defences in the female genital tract to establish systemic infection. As examples, virus particles that avoid entrapment in epithelial surface mucus must breach the mucosal epithelium to interact with submucosal tissue target cells . While pathogen‐induced ulcers and coital abrasions may help HIV‐1 evade genital mucosal barriers , current findings suggest DMPA‐mediated increases in genital mucosal permeability also promote virus transmission.…”

Section: Discussionmentioning

confidence: 82%

Exogenous oestrogen inhibits genital transmission of cell‐associated HIV‐1 in DMPA‐treated humanized mice

et al. 2018

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IntroductionHIV affects more women than any other life‐threatening infectious agent, and most infections are sexually transmitted. HIV must breach the female genital tract mucosal barrier to establish systemic infection, and clinical studies indicate virus more easily evades this barrier in women using depot‐medroxyprogesterone acetate (DMPA) and other injectable progestins for contraception. Identifying a potential mechanism for this association, we learned DMPA promotes susceptibility of wild‐type mice to genital herpes simplex virus type 2 (HSV‐2) infection by reducing genital tissue expression of the cell‐cell adhesion molecule desmoglein‐1 (DSG‐1) and increasing genital mucosal permeability. Conversely, DMPA‐mediated increases in genital mucosal permeability and HSV‐2 susceptibility were eliminated in mice concomitantly administered exogenous oestrogen (E). To confirm and extend these findings, herein we used humanized mice to define effects of systemic DMPA and intravaginal (ivag) E administration on susceptibility to genital infection with cell‐associated HIV‐1.MethodsEffects of DMPA or an intravaginal (ivag) E cream on engraftment of NOD‐scid‐IL‐2Rgcnull (NSG) mice with human peripheral blood mononuclear cells (hPBMCs) were defined with flow cytometry. Confocal microscopy was used to evaluate effects of DMPA, DMPA and E cream, or DMPA and the pharmacologically active component of the cream on vaginal tissue DSG‐1 expression and genital mucosal permeability to low molecular weight (LMW) molecules and hPBMCs. In other studies, hPBMC‐engrafted NSG mice (hPBMC‐NSG) received DMPA or DMPA and ivag E cream before genital inoculation with 106 HIV‐1‐infected hPBMCs. Mice were euthanized 10 days after infection, and plasma HIV‐1 load quantified by qRT‐PCR and splenocytes used to detect HIV‐1 p24 antigen via immunohistochemistry and infectious virus via TZM‐bl luciferase assay.ResultsWhereas hPBMC engraftment was unaffected by DMPA or E treatment, mice administered DMPA and E (cream or the pharmacologically active cream component) displayed greater vaginal tissue expression of DSG‐1 protein and decreased vaginal mucosal permeability to LMW molecules and hPBMCs versus DMPA‐treated mice. DMPA‐treated hPBMC‐NSG mice were also uniformly susceptible to genital transmission of cell‐associated HIV‐1, while no animal concomitantly administered DMPA and E cream acquired systemic HIV‐1 infection.ConclusionExogenous E administration reduces susceptibility of DMPA‐treated humanized mice to genital HIV‐1 infection.

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“…293T cells were seeded in 6-well plates (Falcon) at a concentration of 3x10 5 cells/well, and transfected the next day using FuGENE (Promega) with 0.5 μg/well of the F4.GFP or F4.HSA proviral constructs previously described (Cavrois et al, 2017;Ma et al, 2020;Neidleman et al, 2017). Supernatants from the cultures were harvested after 2 days and p24 Gag concentrations were measured with a Lenti-X p24 Rapid Titer kit (Clontech).…”

Section: Viral Productionmentioning

confidence: 99%

“…cocktail of ART fully suppresses HIV infection. PHA-activated PBMCs were mock-treated or exposed to the CCR5-tropic HIV-1 reporter strain F4.GFP (Neidleman et al, 2017), either in the absence or presence of a cocktail of ART drugs targeting HIV-1 Reverse Transcriptase, Protease, and Integrase, as well as the fusion inhibitor T20. Cells were then analyzed by FACS 4 days later for infection levels.…”

Section: Figure S2 Establishing Conditions For Ex Vivo Reactivation mentioning

confidence: 99%

The Atlas of the In Vivo HIV CD4 T Cell Reservoir

Neidleman

Luo

Frouard

et al. 2020

Preprint

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The latent reservoir is a main barrier for curing HIV. But because latently-infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently-infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. Most importantly, by selecting 8-10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells, thereby validating the PP-SLIDE approach for reservoir characterization. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies of HIV persistence.

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Mucosal stromal fibroblasts markedly enhance HIV infection of CD4+ T cells

Cited by 54 publications

References 70 publications

Estradiol‐regulated innate antiviral responses of human endometrial stromal fibroblasts

Estradiol‐regulated innate antiviral responses of human endometrial stromal fibroblasts

Exogenous oestrogen inhibits genital transmission of cell‐associated HIV‐1 in DMPA‐treated humanized mice

The Atlas of the In Vivo HIV CD4 T Cell Reservoir

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