Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

Introini, Andrea; Boström, Stéphanie; Bradley, Frideborg; Gibbs, Anna; Glaessgen, Axel; Tjernlund, Annelie; Broliden, Kristina

doi:10.1371/journal.ppat.1006402

Cited by 34 publications

(46 citation statements)

References 84 publications

(127 reference statements)

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“…produce ␤-chemokines than other antiviral cytokines (27). Overall these data, combined with observations from ectocervical explants exposed to SP (15), begin to portray a more comprehensive description of the impact of SP on mucosal immunity to HIV-1. In addition to possible epithelial cell production of RANTES (15), SP is capable of eliciting RANTES secretion by T cells.…”

Section: Discussionmentioning

confidence: 80%

“…Our in vitro data suggest that SP induces the secretion of ␤-chemokines over the course of 16 h after SP exposure. Combined with data from tissue explants demonstrating production of RANTES in response to SP (15), it seems clear that SP exposure likely results in elevated CCR5 ligand concentrations in the genital tract. In vitro, this manifests as reductions in T cell surface CCR5 expression, but in vivo, it is unclear whether CCR5 might be similarly downregulated or whether increased frequencies of CCR5 ϩ T cells might traffick to the vaginal mucosa.…”

Section: Figmentioning

confidence: 98%

“…While in vitro studies of ectocervical explants exposed to SP have demonstrated SP to induce RANTES secretion (15), the contribution of lymphoid cells versus epithelial cells to CCR5 ligand accumulation in this context has not been assessed. The capacity for activated T cells to secrete RANTES and MIP1␣/␤ is well described, and this secretion is an important mechanism by which HIV-1 infection can be suppressed (via CCR5 ligation and internalization) (16).…”

mentioning

confidence: 99%

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Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of In Vitro versus In Vivo Models

Juno

Wragg

Kristensen

et al. 2019

J Virol

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Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that CCR5+ CD4+ T cells are initial targets for HIV-1 infection, the impact of semen on T cell CCR5 expression and ligand production remains inconclusive. To determine if semen modulates the lymphocyte CCR5 receptor/ligand axis, primary human T cell CCR5 expression and natural killer (NK) cell anti-HIV-1 antibody-dependent beta chemokine production was assessed following seminal plasma (SP) exposure. Purified T cells produce sufficient quantities of RANTES to result in a significant decline in CCR5bright T cell frequency following 16 h of SP exposure (P = 0.03). Meanwhile, NK cells retain the capacity to produce limited amounts of MIP-1α/MIP-1β in response to anti-HIV-1 antibody-dependent stimulation (median, 9.5% MIP-1α+ and/or MIP-1β+), despite the immunosuppressive nature of SP. Although these in vitro experiments suggest that SP-induced CCR5 ligand production results in the loss of surface CCR5 expression on CD4+ T cells, the in vivo implications are unclear. We therefore vaginally exposed five pigtail macaques to SP and found that such exposure resulted in an increase in CCR5+ HIV-1 target cells in three of the animals. The in vivo data support a growing body of evidence suggesting that semen exposure recruits target cells to the vagina that are highly susceptible to HIV-1 infection, which has important implications for HIV-1 transmission and vaccine design. IMPORTANCE The majority of HIV-1 vaccine studies do not take into consideration the impact that semen exposure might have on the mucosal immune system. In this study, we demonstrate that seminal plasma (SP) exposure can alter CCR5 expression on T cells. Importantly, in vitro studies of T cells in culture cannot replicate the conditions under which immune cells might be recruited to the genital mucosa in vivo, leading to potentially erroneous conclusions about the impact of semen on mucosal HIV-1 susceptibility.

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Section: Discussionmentioning

confidence: 80%

Section: Figmentioning

confidence: 98%

mentioning

confidence: 99%

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Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of In Vitro versus In Vivo Models

Juno

Wragg

Kristensen

et al. 2019

J Virol

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“…The V3-V4 region of the 16S rRNA gene was amplified using primers F341-R805 as described previously. 30 The following cytokines/chemokines were selected based on their function as inflammation regulators and abundance in CVS as pre- 29 As the V3-V4 region of the 16S rRNA gene is not always variable enough to consistently classify the microbiota to the species levels, genus level was used for further analysis.…”

Section: S Rrna Gene Sequencing Of Vaginal Microbiota and Cytokinmentioning

confidence: 99%

“…Concentrations of cytokines in the CVS samples were measured using a multiplex bead array immunoassay as previously described. 30 The following cytokines/chemokines were selected based on their…”

Section: S Rrna Gene Sequencing Of Vaginal Microbiota and Cytokinmentioning

confidence: 99%

The vaginal microbiome amplifies sex hormone‐associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption

Bradley

Birse

Hasselrot

et al. 2018

American J Rep Immunol

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Extracellular vesicles from seminal plasma interact with T cells in vitro and drive their differentiation into regulatory T‐cells

Zhang,

Greve,

Minh

et al. 2024

J of Extracellular Vesicle

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Seminal plasma induces immune tolerance towards paternal allogenic antigens within the female reproductive tract and during foetal development. Recent evidence suggests a role for extracellular vesicles in seminal plasma (spEVs). We isolated spEVs from seminal plasma that was donated by vasectomized men, thereby excluding any contributions from the testis or epididymis. Previous analysis demonstrated that such isolated spEVs originate mainly from the prostate. Here we observed that when isolated fluorescently labelled spEVs were mixed with peripheral blood mononuclear cells, they were endocytosed predominantly by monocytes, and to a lesser extent also by T‐cells. In a mixed lymphocyte reaction, T‐cell proliferation was inhibited by spEVs. A direct effect of spEVs on T‐cells was demonstrated when isolated T cells were activated by anti‐CD3/CD28 coated beads. Again, spEVs interfered with T cell proliferation, as well as with the expression of CD25 and the release of IFN‐γ, TNF, and IL‐2. Moreover, spEVs stimulated the expression of Foxp3 and IL‐10 by CD4+CD25+CD127‐ T cells, indicating differentiation into regulatory T‐cells (Tregs). Prior treatment of spEVs with proteinase K revoked their effects on T‐cells, indicating a requirement for surface‐exposed spEV proteins. The adenosine A2A receptor‐specific antagonist CPI‐444 also reduced effects of spEVs on T‐cells, consistent with the notion that the development of Tregs and their immune suppressive functions are under the influence of adenosine‐A2A receptor signalling. We found that adenosine is highly enriched in spEVs and propose that spEVs are targeted to and endocytosed by T‐cells, after which they may release their adenosine content into the lumen of endosomes, thus allowing endosome‐localized A2A receptor signalling in spEVs targeted T‐cells. Collectively, these data support the idea that spEVs can prime T cells directly for differentiation into Tregs.

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Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

Cited by 34 publications

References 84 publications

Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of In Vitro versus In Vivo Models

Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of In Vitro versus In Vivo Models

The vaginal microbiome amplifies sex hormone‐associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption

Extracellular vesicles from seminal plasma interact with T cells in vitro and drive their differentiation into regulatory T‐cells

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