ABSTRACT
Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels.
Subject(s)
Host-Pathogen Interactions/drug effects , Macrophages/drug effects , Mucous Membrane/drug effects , Progestins/therapeutic use , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus/drug effects , Vagina/drug effects , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/virology , Cervix Uteri/drug effects , Cervix Uteri/immunology , Cervix Uteri/metabolism , Cervix Uteri/virology , Delayed-Action Preparations , Female , Injections, Intramuscular , Lymphocyte Activation/drug effects , Macaca mulatta , Macaca nemestrina , Macrophage Activation/drug effects , Macrophages/immunology , Macrophages/metabolism , Macrophages/virology , Medroxyprogesterone Acetate/administration & dosage , Medroxyprogesterone Acetate/therapeutic use , Menstrual Cycle , Mucous Membrane/immunology , Mucous Membrane/metabolism , Mucous Membrane/virology , Progestins/administration & dosage , Progestins/metabolism , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/immunology , Simian Immunodeficiency Virus/physiology , Vagina/immunology , Vagina/metabolism , Vagina/virology , Virus Internalization/drug effectsABSTRACT
Human papillomaviruses (HPV) infect stratified epithelia and link their life cycles to epithelial differentiation. The HPV E5 protein plays a role in the productive phase of the HPV life cycle but its mechanism of action is still unclear. We identify a new binding partner of E5, A4, using a membrane-associated yeast-two hybrid system. The A4 protein co-localizes with HPV 31 E5 in perinuclear regions and forms complexes with E5 and Bap31. In normal keratinocytes, A4 is found primarily in basal cells while in HPV positive cells high levels of A4 are seen in both undifferentiated and differentiated cells. Reduction of A4 expression by shRNAs, enhanced HPV genome amplification and increased cell proliferation ability following differentiation but this was not seen in cells lacking E5. Our studies suggest that the A4 protein is an important E5 binding partner that plays a role in regulating cell proliferation ability upon differentiation.