Sex hormones selectively impact the endocervical mucosal microenvironment: implications for HIV transmission.
Several studies suggest that progesterone and estrogens may affect HIV transmission in different, possibly opposing ways. Nonetheless, a direct comparison of their effects on the mucosal immune system has never been done. We hypothesize that sex hormones might impact the availability of cells and immune factors important in early stages of mucosal transmission, and, in doing so influence the risk of HIV acquisition. To test this hypothesis, we employed 15 ovarectomized rhesus macaques: 5 were treated with Depot Medroxy Progesterone Acetate (DMPA), 6 with 17-β estradiol (E2) and 4 were left untreated. All animals were euthanized 5 weeks after the initiation of hormone treatment, a time post-DMPA injection associated with high susceptibility to SIV infection. We found that DMPA-treated macaques exhibited higher expression of integrin α4β7 (α4β7) on CD4+ T cells, the gut homing receptor and a marker of cells highly susceptible to HIV, in the endocervix than did the E2-treated animals. In contrast, the frequency of CCR5+ CD4+ T cells in DMPA-treated macaques was higher than in the E2-treated group in vaginal tissue, but lower in endocervix. α4β7 expression on dendritic cells (DCs) was higher in the DMPA-treated group in the endocervical tissue, but lower in vaginal tissue and on blood DCs compared with the E2-treated animals. Soluble MAdCAM-1, the α4β7 ligand, was present in the vaginal fluids of the control and E2-treated groups, but absent in the fluids from DMPA-treated animals. Both hormones modulated the expression and release of inflammatory factors and modified the distribution of sialomucins in the endocervix. In summary, we found that sex hormones profoundly impact mucosal immune factors that are directly implicated in HIV transmission. The effect is particularly significant in the endocervix. This may increase our understanding of the potential hormone-driven modulation of HIV susceptibility and potentially guide contraceptive policies in high-risk settings.
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Diana
D
Goode
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Meropi
M
Aravantinou
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Sebastian
S
Jarl
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Rosaline
R
Truong
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Nina
N
Derby
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Natalia
N
Guerra-Perez
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Jessica
J
Kenney
Tulane National Primate Research Center, Tulane University Sciences Center, Covington, Louisiana, United States of America.
James
J
Blanchard
Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
Agegnehu
A
Gettie
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Melissa
M
Robbiani
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Elena
E
Martinelli
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002584:Cervix Uteri / Q000187:drug effects / Q000378:metabolism*; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000635:transmission*; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism
D054421:Chemokine CCL21; D054407:Chemokine CCL4; D004967:Estrogens; D039641:Integrin beta Chains; D009077:Mucins; D019713:Receptors, CCR5; C091368:integrin beta7; D039441:Integrin alpha4; D004958:Estradiol; D017258:Medroxyprogesterone Acetate