scholarly journals Nanoparticles containing siRNA to silence CD4 and CCR5 reduce expression of these receptors and inhibit HIV-1 infection in human female reproductive tract tissue explants

2011 ◽  
Vol 3 (2) ◽  
pp. 11 ◽  
Author(s):  
Susan K. Eszterhas ◽  
Nicole O. Ilonzo ◽  
Jennifer E. Crozier ◽  
Stela Celaj ◽  
Alexandra L. Howell
Keyword(s):  
Messenger Rna ◽  
Reproductive Tract ◽  
Antiviral Effect ◽  
Female Reproductive Tract ◽  
Target Cells ◽  
Human Female ◽  
Sirna Transfection ◽  
Tissue Explants ◽  
Hiv 1

Human Immunodeficiency Virus-type 1 (HIV- 1) binds to CD4 and CCR5 receptors on target cells in the human female reproductive tract. We sought to determine whether reducing levels of messenger RNA (mRNA) transcripts that encode these receptors in female reproductive tract cells could protect mucosal tissue explants from HIV- 1 infection. Explants prepared from the endometrium, endocervix, and ectocervix of hysterectomy tissues from HIV-1 sero-negative women were exposed to nanoparticles containing CD4- and CCR5-specific short-interfering RNA (siRNA) sequences. Explants were then exposed two days later to HIV-1, and HIV-1 reverse transcripts were measured five days post-infection. Explants treated with nanoparticles containing CD4- and CCR5-specific siRNA showed reduced levels of CD4 and CCR5 transcripts, and significantly lower levels of HIV-1 reverse transcripts compared to those treated with an irrelevant siRNA. In female reproductive tract explants and in peripheral blood cell cultures, siRNA transfection induced the secretion of IFN-alpha (IFN-α), a potent antiviral cytokine. In female mice, murine-specific Cd4-siRNA nanoparticles instilled within the uterus significantly reduced murine Cd4 transcripts by day 3. Our findings demonstrate that siRNA nanoparticles reduce expression of HIV-1 infectivity receptors in human female reproductive tract tissues and also inhibit HIV-1 infection. Murine studies demonstrate that nanoparticles can penetrate the reproductive tract tissues in vivo and silence gene expression. The induction of IFN-α after siRNA transfection can potentially contribute to the antiviral effect. These findings support the therapeutic development of nanoparticles to deliver siRNA molecules to silence host cell receptors in the female reproductive tract as a novel microbicide to inhibit mucosal HIV-1 transmission.

scholarly journals Organoid systems to study the human female reproductive tract and pregnancy

2020 ◽  
Vol 28 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Lama Alzamil ◽  
Konstantina Nikolakopoulou ◽  
Margherita Y. Turco
Keyword(s):  
Pregnancy Outcome ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Fallopian Tubes ◽  
Human Female ◽  
Placental Development ◽  
Recent Developments ◽  
Opening Up

AbstractBoth the proper functioning of the female reproductive tract (FRT) and normal placental development are essential for women’s health, wellbeing, and pregnancy outcome. The study of the FRT in humans has been challenging due to limitations in the in vitro and in vivo tools available. Recent developments in 3D organoid technology that model the different regions of the FRT include organoids of the ovaries, fallopian tubes, endometrium and cervix, as well as placental trophoblast. These models are opening up new avenues to investigate the normal biology and pathology of the FRT. In this review, we discuss the advances, potential, and limitations of organoid cultures of the human FRT.

scholarly journals Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues

2015 ◽  
Vol 89 (10) ◽  
pp. 5569-5580 ◽  
Author(s):  
Shannon A. Allen ◽  
Ann M. Carias ◽  
Meegan R. Anderson ◽  
Eneniziaogochukwu A. Okocha ◽  
Lorie Benning ◽  
...  
Keyword(s):  
Cell Culture ◽  
Virus Infection ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Female Reproductive Tract ◽  
Productive Infection ◽  
Target Cells ◽  
Mucosal Transmission ◽  
Epithelial Barriers ◽  
Hiv 1

ABSTRACTThe majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur in women when semen harboring infectious virus is deposited onto the mucosal barriers of the vaginal, ectocervical, and endocervical epithelia. Seminal factors such as semen-derived enhancer of virus infection (SEVI) fibrils were previously shown to greatly enhance the infectivity of HIV-1 in cell culture systems. However, when SEVI is intravaginally applied to living animals, there is no effect on vaginal transmission. To define how SEVI might function in the context of sexual transmission, we applied HIV-1 and SEVI to intact human and rhesus macaque reproductive tract tissues to determine how it influences virus interactions with these barriers. We show that SEVI binds HIV-1 and sequesters most virions to the luminal surface of the stratified squamous epithelium, significantly reducing the number of virions that penetrated the tissue. In the simple columnar epithelium, SEVI was no longer fibrillar in structure and was detached from virions but allowed significantly deeper epithelial virus penetration. These observations reveal that the action of SEVI in intact tissues is very different in the anatomical context of sexual transmission and begin to explain the lack of stimulation of infection observed in the highly relevant mucosal transmission model.IMPORTANCEThe most common mode of HIV-1 transmission in women occurs via genital exposure to the semen of HIV-infected men. A productive infection requires the virus to penetrate female reproductive tract epithelial barriers to infect underlying target cells. Certain factors identified within semen, termed semen-derived enhancers of virus infection (SEVI), have been shown to significantly enhance HIV-1 infectivity in cell culture. However, when applied to the genital tracts of living female macaques, SEVI did not enhance virus transmission. Here we show that SEVI functions very differently in the context of intact mucosal tissues. SEVI decreases HIV-1 penetration of squamous epithelial barriers in humans and macaques. At the mucus-coated columnar epithelial barrier, the HIV-1/SEVI interaction is disrupted. These observations suggest that SEVI may not play a significant stimulatory role in the efficiency of male-to-female sexual transmission of HIV.

scholarly journals Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Michelle D. Cherne ◽  
Amy L. Cole ◽  
Lisa Newberry ◽  
Mary Schmidt-Owens ◽  
Michael Deichen ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Hiv Infection ◽  
Bacterial Vaginosis ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Target Cells ◽  
Barrier Dysfunction ◽  
Host Matrix ◽  
Mmp Inhibitor ◽  
Hiv 1

ABSTRACT Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy Lactobacillus-dominant microflora is replaced by BV-associated bacteria (BVAB), can significantly increase the incidence of human immunodeficiency virus (HIV) acquisition. Discerning the effect of BV on the mucosal epithelium of the FRT may yield novel preventatives and therapeutics for HIV infection. Here, we investigated barrier dysfunction of the endocervix by host-derived factors, secreted in response to BV, as a potential cause of HIV infection. Using a polarized endocervical cell culture system, we determined that conditioned media (CM) from endocervical cells cocultured with BVAB (endocervical+BVAB CM), as well as cervicovaginal fluid (CVF) from women with BV, disrupted epithelial polarization. We assessed host matrix metalloproteinases (MMPs) as the BV-associated secreted factors which disrupt the endocervical epithelium. MMPs were overexpressed in endocervical+BVAB CM and CVF from women with BV and were capable of disrupting endocervical epithelial polarization. When we cocultured polarized endocervical cells with HIV-1-infected lymphocyte-derived cells, we discovered endocervical+BVAB CM and MMPs significantly increased the transmigration of virus through the epithelium, and treatment with an MMP inhibitor decreased these effects. When we examined the effect of CVF on HIV-1 transmigration through endocervical epithelium, we demonstrated that CVF samples with greater concentrations of BV-associated MMPs increased viral transmigration. Our results suggest MMPs increase HIV-1 infection by disrupting the endocervical epithelium, permitting transmigration of virus through the epithelium to infect underlying target cells.

scholarly journals ORIGINAL ARTICLE: CCL20/MIP3α is a Novel Anti-HIV-1 Molecule of the Human Female Reproductive Tract

2009 ◽  
Vol 62 (1) ◽  
pp. 60-71 ◽  
Author(s):  
Mimi Ghosh ◽  
Zheng Shen ◽  
Todd M. Schaefer ◽  
John V. Fahey ◽  
Phalguni Gupta ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Human Female ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Distinct Characteristics of Endometrial and Decidual Macrophages and Regulation of Their Permissivity to HIV-1 Infection by SAMHD1

2014 ◽  
Vol 89 (2) ◽  
pp. 1329-1339 ◽  
Author(s):  
Héloïse Quillay ◽  
Hicham El Costa ◽  
Romain Marlin ◽  
Marion Duriez ◽  
Claude Cannou ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
The Body ◽  
Target Cells ◽  
Mucosal Protection ◽  
Protective Mechanisms ◽  
Mucosal Transmission ◽  
Uterine Mucosa ◽  
Hiv 1

ABSTRACTIn order to develop strategies to prevent HIV-1 (human immunodeficiency virus type 1) transmission, it is crucial to better characterize HIV-1 target cells in the female reproductive tract (FRT) mucosae and to identify effective innate responses. Control of HIV-1 infection in the decidua (the uterine mucosa during pregnancy) can serve as a model to study natural mucosal protection. Macrophages are the main HIV-1 target cells in the decidua. Here we report thatin vitro, macrophages and T cells are the main HIV-1 targets in the endometrium in nonpregnant women. As reported for decidual macrophages (dM), endometrial macrophages (eM) were found to have an M2-like phenotype (CD68+CD163+CD206+IL-10high). However, eM and dM may belong to different subpopulations, as they differently express certain markers and secrete different amounts of proinflammatory and anti-inflammatory cytokines. We observed strong expression of the SAMHD1 restriction factor and weak expression of its inactive form (pSAMHD1, phosphorylated at residue Thr592) in both eM and dM. Infection of macrophages from both tissues was enhanced in the presence of the viral protein Vpx, suggesting a role for SAMHD1 in the restriction of HIV-1 infection. This study and further comparisons of the decidua with FRT mucosae in nonpregnant women should help to identify mechanisms of mucosal protection against HIV-1 infection.IMPORTANCEThe female reproductive tract mucosae are major portals of HIV-1 entry into the body. The decidua (uterine mucosa during pregnancy) can serve as a model for studying natural mucosal protection against HIV-1 transmission. A comparison of target cells and innate responses in the decidua versus the endometrium in nonpregnant women could help to identify protective mechanisms. Here, we report for the first time that macrophages are one of the main HIV-1 target cells in the endometrium and that infection of macrophages from both the endometrium and the decidua is restricted by SAMHD1. These findings might have implications for the development of vaccines to prevent HIV-1 mucosal transmission.

scholarly journals Rapid-Release Griffithsin Fibers for Dual Prevention of HSV-2 and HIV-1 Infections

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Kevin M. Tyo ◽  
Amanda B. Lasnik ◽  
Longyun Zhang ◽  
Alfred B. Jenson ◽  
Joshua L. Fuqua ◽  
...  
Keyword(s):  
Murine Model ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vaginal Tissue ◽  
Vaginal Lavage ◽  
Rapid Release ◽  
Hiv 1

ABSTRACT The biologic griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs), including human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP) fibers that incorporate GRFT in in vitro (HIV-1 and HSV-2) and in vivo (HSV-2) infection models. GRFT loading was determined via enzyme-linked immunosorbent assay (ELISA), and the bioactivity of GRFT fibers was assessed using in vitro HIV-1 pseudovirus and HSV-2 plaque assays. Afterwards, the efficacy of GRFT fibers was assessed in a murine model of lethal HSV-2 infection. Finally, murine reproductive tracts and vaginal lavage samples were evaluated for histology and cytokine expression, 24 and 72 h after fiber administration, to determine safety. All rapid-release formulations achieved high levels of GRFT incorporation and were completely efficacious against in vitro HIV-1 and HSV-2 infections. Importantly, all rapid-release GRFT fibers provided potent protection in a murine model of HSV-2 infection. Moreover, histology and cytokine levels, evaluated from collected murine reproductive tissues and vaginal lavage samples treated with blank fibers, showed no increased cytokine production or histological aberrations, demonstrating the preliminary safety of rapid-release GRFT fibers in vaginal tissue.

Effect of Contraceptive Steroids on the Endometrium of Guinea Pig: SEM study

1977 ◽  
Vol 35 ◽  
pp. 668-669
Author(s):  
Mai M. Said ◽  
Ramesh K. Nayak ◽  
Randall E. McCoy
Keyword(s):  
Guinea Pig ◽  
Reproductive Tract ◽  
Three Dimensional ◽  
Female Reproductive Tract ◽  
Human Female ◽  
Surface Ultrastructure ◽  
Transmission Electron ◽  
Sem Study ◽  
Uterine Mucosa ◽  
Group 1

Burgos and Wislocki described changes in the mucosa of the guinea pig uterus, cervix and vagina during the estrous cycle investigated by transmission electron microscopy. More recently, Moghissi and Reame reported the effects of progestational agents on the human female reproductive tract. They found drooping and shortening of cilia in norgestrel and norethindrone- treated endometria. To the best of our knowledge, no studies concerning the effects of mestranol and norethindrone given concurrently on the three-dimensional surface features on the uterine mucosa of the guinea pig have been reported. The purpose of this study was to determine the effect of mestranol and norethindrone on surface ultrastructure of guinea pig uterus by SEM.Seventy eight animals were used in this study. They were allocated into two groups. Group 1 (20 animals) was injected intramuscularly 0.1 ml vegetable oil and served as controls.

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