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Modulation of the CCR5 receptor/ligand axis by seminal plasma and the utility of in vitro versus in vivo models

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  • Jennifer A Juno, Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia mattp@unimelb.edu.au jennifer.juno@unimelb.edu.au.
  • ,
  • Kathleen M Wragg, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • ,
  • Anne B Kristensen
  • Wen Shi Lee, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • ,
  • Kevin J Selva, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • ,
  • Renee M van der Sluis
  • Anthony D Kelleher, The Kirby Institute, UNSW Sydney, New South Wales, Australia.
  • ,
  • Benjamin R Bavinton, The Kirby Institute, UNSW Sydney, New South Wales, Australia.
  • ,
  • Andrew E Grulich, The Kirby Institute, UNSW Sydney, New South Wales, Australia.
  • ,
  • Sharon R Lewin, Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.
  • ,
  • Stephen J Kent, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Melbourne, Victoria, Australia.
  • ,
  • Matthew S Parsons, Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia mattp@unimelb.edu.au jennifer.juno@unimelb.edu.au.

Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggests CCR5+CD4+ T cells are initial targets for HIV-1 infection, the impact of semen on T cell CCR5 expression and ligand production remains inconclusive. To determine if semen modulates the lymphocyte CCR5 receptor/ligand axis, primary human T cell CCR5 expression and natural killer (NK) cell anti-HIV-1 antibody-dependent beta chemokine production was assessed following seminal plasma (SP) exposure. Purified T cells produce sufficient quantities of RANTES to result in a significant decline in CCR5bright T cell frequency following 16 hours of SP exposure (p=0.03). Meanwhile NK cells retain the capacity to produce limited amounts of MIP-1α/MIP-1β in response to anti-HIV-1 antibody-dependent stimulation (median 9.5% MIP-1α+MIP-1β+), despite the immunosuppressive nature of SP. Although these in vitro experiments suggest that SP-induced CCR5 ligand production results in the loss of surface CCR5 expression on CD4+ T cells, the in vivo implications are unclear. We therefore vaginally exposed five pigtail macaques to SP and found that such exposure resulted in an increase in CCR5+ HIV-1 target cells in three out of five animals. The in vivo data support a growing body of evidence suggesting that semen exposure recruits target cells to the vagina that are highly susceptible to HIV-1 infection, which has important implications for HIV-1 transmission and vaccine design.IMPORTANCE The majority of HIV-1 vaccine studies do not take into consideration the impact that semen exposure might have on the mucosal immune system. In this study, we demonstrate that seminal plasma (SP) exposure can alter CCR5 expression on T cells. Importantly, in vitro studies of T cells in culture cannot replicate the conditions under which immune cells might be recruited to the genital mucosa in vivo, leading to potentially erroneous conclusions about the impact of semen on mucosal HIV-1 susceptibility.

OriginalsprogEngelsk
TidsskriftJournal of Virology
ISSN0022-538X
DOI
StatusE-pub ahead of print - 13 mar. 2019
Eksternt udgivetJa

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