Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice
Abstract The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/2c3623001ed1450a83368b237c5f59e6 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:2c3623001ed1450a83368b237c5f59e6 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:2c3623001ed1450a83368b237c5f59e62021-12-02T10:54:06ZDepot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice10.1038/s41598-021-83242-92045-2322https://doaj.org/article/2c3623001ed1450a83368b237c5f59e62021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83242-9https://doaj.org/toc/2045-2322Abstract The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1 tm1Mom Il2rg tm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.Jocelyn M. WesselsPhilip V. NguyenDanielle VitaliKristen MuellerFatemeh VahediAllison M. FelkerHaley A. DupontPuja BagriChris P. VerschoorAlexandre DeshiereTony MazzulliMichel J. TremblayAli A. AshkarCharu KaushicNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Jocelyn M. Wessels Philip V. Nguyen Danielle Vitali Kristen Mueller Fatemeh Vahedi Allison M. Felker Haley A. Dupont Puja Bagri Chris P. Verschoor Alexandre Deshiere Tony Mazzulli Michel J. Tremblay Ali A. Ashkar Charu Kaushic Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice |
| description |
Abstract The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1 tm1Mom Il2rg tm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women. |
| format |
article |
| author |
Jocelyn M. Wessels Philip V. Nguyen Danielle Vitali Kristen Mueller Fatemeh Vahedi Allison M. Felker Haley A. Dupont Puja Bagri Chris P. Verschoor Alexandre Deshiere Tony Mazzulli Michel J. Tremblay Ali A. Ashkar Charu Kaushic |
| author_facet |
Jocelyn M. Wessels Philip V. Nguyen Danielle Vitali Kristen Mueller Fatemeh Vahedi Allison M. Felker Haley A. Dupont Puja Bagri Chris P. Verschoor Alexandre Deshiere Tony Mazzulli Michel J. Tremblay Ali A. Ashkar Charu Kaushic |
| author_sort |
Jocelyn M. Wessels |
| title |
Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice |
| title_short |
Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice |
| title_full |
Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice |
| title_fullStr |
Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice |
| title_full_unstemmed |
Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice |
| title_sort |
depot medroxyprogesterone acetate (dmpa) enhances susceptibility and increases the window of vulnerability to hiv-1 in humanized mice |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/2c3623001ed1450a83368b237c5f59e6 |
| work_keys_str_mv |
AT jocelynmwessels depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT philipvnguyen depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT daniellevitali depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT kristenmueller depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT fatemehvahedi depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT allisonmfelker depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT haleyadupont depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT pujabagri depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT chrispverschoor depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT alexandredeshiere depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT tonymazzulli depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT micheljtremblay depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT aliaashkar depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice AT charukaushic depotmedroxyprogesteroneacetatedmpaenhancessusceptibilityandincreasesthewindowofvulnerabilitytohiv1inhumanizedmice |
| _version_ |
1718396460162088960 |