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) ◽  
Author(s):  
Susan K. Eszterhas ◽  
Nicole O. Ilonzo ◽  
Jennifer E. Crozier ◽  
Stela Celaj ◽  
Alexandra L. Howell
2011 ◽  
Vol 3 (2) ◽  
pp. 11 ◽  
Author(s):  
Susan K. Eszterhas ◽  
Nicole O. Ilonzo ◽  
Jennifer E. Crozier ◽  
Stela Celaj ◽  
Alexandra L. Howell

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.


2009 ◽  
Vol 62 (1) ◽  
pp. 60-71 ◽  
Author(s):  
Mimi Ghosh ◽  
Zheng Shen ◽  
Todd M. Schaefer ◽  
John V. Fahey ◽  
Phalguni Gupta ◽  
...  

Author(s):  
Mai M. Said ◽  
Ramesh K. Nayak ◽  
Randall E. McCoy

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.


2005 ◽  
Vol 2 (1) ◽  
pp. 35-38 ◽  
Author(s):  
Alexandra L. Howell ◽  
Susana N. Asin ◽  
Grant R. Yeaman ◽  
Charles R. Wira

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3176
Author(s):  
Sharon M. Anderson ◽  
Andrea R. Thurman ◽  
Neelima Chandra ◽  
Suzanne S. Jackson ◽  
Susana Asin ◽  
...  

While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.


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