title: High-risk oncogenic HPV genotype infection associates with increased immune activation and T cell exhaustion in ART-suppressed HIV-1-infected women.
abstract: Persistence of human papillomavirus (HPV) and cervical disease in the context of HIV co-infection can be influenced by introduction of antiretroviral therapy (ART) and sustained immune activation despite ART. We conducted a cross-sectional study in order to evaluate immune activation/exhaustion in ART-suppressed HIV(+) women with or without high-risk (HR) HPV-related cervical intraepithelial neoplasia (CIN). 55 South African women were recruited in three groups: HR (-) (n = 16) and HR (+) (n = 15) HPV with negative cervical histopathology, and HR (+) HPV with CIN grade 1/2/3 (n = 24). Sampling included endocervical brushing (HPV DNA genotyping), Pap smear (cytology), colposcopic punch biopsy (histopathology, histochemical evaluation of immune cells), and peripheral blood (clinical assessment, flow cytometry-based immune subset characterization). Statistics were done using R2.5.1. Irrespective of the presence of CIN, HR (+) HPV women had higher circulating levels of T cells expressing markers of activation/exhaustion (CD38, PD1, CTLA-4, BTLA, CD160), Tregs, and myeloid subsets expressing corresponding ligands (PDL1, PDL2, CD86, CD40, HVEM) than HR (-) HPV women. A decrease in circulating NK cells was associated with CIN grade. CD4(+) T cell count associated negatively with T cell exhaustion and expression of negative regulators on myeloid cells. Women with CIN when compared to HR (-) HPV women, had higher cervical cell density in stroma and epithelium for CD4(+), CD68(+), and CD11c(+) cells, and only in stroma for CD8(+) cells. We conclude that in ART-suppressed HIV-infected women with HPV co-infection the levels of T and myeloid cell activation/exhaustion are associated with the presence of HR HPV genotypes.
authors.affiliation: The Wistar Institute , Philadelphia, PA, USA.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Papasavvas
authors.affiliation: Division of Molecular Pathology, Hospital of the University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Lea F
authors.initials: LF
authors.lastname: Surrey
authors.affiliation: Faculty of Health Science Department of Molecular Medicine and Haematology, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Service, Johannesburg, South Africa.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Glencross
authors.affiliation: The Wistar Institute , Philadelphia, PA, USA.
authors.forename: Livio
authors.initials: L
authors.lastname: Azzoni
authors.affiliation: The Wistar Institute , Philadelphia, PA, USA.
authors.forename: Jocelin
authors.initials: J
authors.lastname: Joseph
authors.affiliation: National Health Laboratory Service, Johannesburg, South Africa; Faculty of Health Science Department of Anatomical Pathology, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Tanvier
authors.initials: T
authors.lastname: Omar
authors.affiliation: Division of Surgical Pathology, Hospital of the University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa; National Health Laboratory Service, Cape Town, South Africa.
authors.forename: Anna-Lise
authors.initials: AL
authors.lastname: Williamson
authors.affiliation: Faculty of Health Science Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa; Right to Care, Johannesburg, South Africa.
authors.forename: Maureen
authors.initials: M
authors.lastname: Siminya
authors.affiliation: Faculty of Health Science Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa; Right to Care, Johannesburg, South Africa.
authors.forename: Avril
authors.initials: A
authors.lastname: Swarts
authors.affiliation: The Wistar Institute , Philadelphia, PA, USA.
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Yin
authors.affiliation: The Wistar Institute , Philadelphia, PA, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Faculty of Health Science Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa; Right to Care, Johannesburg, South Africa.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Firnhaber
authors.affiliation: The Wistar Institute , Philadelphia, PA, USA.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
keywords: ART; Activation; HIV; HPV; exhaustion