title: Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility.
abstract: The variable infectivity and transmissibility of HIV/SHIV has been recently associated with the menstrual cycle, with particular susceptibility observed during the luteal phase in nonhuman primate models and ex vivo human explant cultures, but the mechanism is poorly understood. Here, we performed an unbiased, mass spectrometry-based proteomic analysis to better understand the mucosal immunological processes underpinning this observed susceptibility to HIV infection. Cervicovaginal lavage samples (n = 19) were collected, characterized as follicular or luteal phase using days since last menstrual period, and analyzed by tandem mass spectrometry. Biological insights from these data were gained using a spectrum of computational methods, including hierarchical clustering, pathway analysis, gene set enrichment analysis, and partial least-squares discriminant analysis with LASSO feature selection. Of the 384 proteins identified, 43 were differentially abundant between phases (P < 0.05, ≥2-fold change). Cell-cell adhesion proteins and antiproteases were reduced, and leukocyte recruitment (interleukin-8 pathway, P = 1.41E-5) and extravasation proteins (P = 5.62E-4) were elevated during the luteal phase. LASSO/PLSDA identified a minimal profile of 18 proteins that best distinguished the luteal phase. This profile included cytoskeletal elements and proteases known to be involved in cellular movement. Gene set enrichment analysis associated CD4(+) T cell and neutrophil gene set signatures with the luteal phase (P < 0.05). Taken together, our findings indicate a strong association between proteins involved in tissue remodeling and leukocyte infiltration with the luteal phase, which may represent potential hormone-associated mechanisms of increased susceptibility to HIV.
  
  
  OBJECTIVE
  Recent studies have discovered an enhanced susceptibility to HIV infection during the progesterone-dominant luteal phase of the menstrual cycle. However, the mechanism responsible for this enhanced susceptibility has not yet been determined. Understanding the source of this vulnerability will be important for designing efficacious HIV prevention technologies for women. Furthermore, these findings may also be extrapolated to better understand the impact of exogenous hormone application, such as the use of hormonal contraceptives, on HIV acquisition risk. Hormonal contraceptives are the most widely used contraceptive method in sub-Saharan Africa, the most HIV-burdened area of the world. For this reason, research conducted to better understand how hormones impact host immunity and susceptibility factors important for HIV infection is a global health priority.
authors.affiliation: National Lab for HIV Immunology, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Manitoba, Canada Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada ummogkk@myumanitoba.ca.
authors.forename: Kenzie
authors.initials: K
authors.lastname: Birse
authors.affiliation: Department of Biological Engineering and Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Kelly B
authors.initials: KB
authors.lastname: Arnold
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Novak
authors.affiliation: Mass Spectrometry Core Facility, National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
authors.forename: Stuart
authors.initials: S
authors.lastname: McCorrister
authors.affiliation: Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Souradet
authors.initials: S
authors.lastname: Shaw
authors.affiliation: Mass Spectrometry Core Facility, National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Westmacott
authors.affiliation: National Lab for HIV Immunology, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Manitoba, Canada Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada Department of Medical Microbiology, University of Nairobi, Department of Medical Microbiology, Nairobi, Kenya.
authors.forename: Terry B
authors.initials: TB
authors.lastname: Ball
authors.affiliation: Department of Biological Engineering and Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: National Lab for HIV Immunology, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Manitoba, Canada Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada Unit of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Burgener
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004198:Disease Susceptibility / Q000276:immunology*; D004848:Epithelium / Q000276:immunology*; D005260:Female; D005498:Follicular Phase / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D008183:Luteal Phase / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C508606:CXCL8 protein, human; D015815:Cell Adhesion Molecules; D016209:Interleukin-8