Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of in Vitro versus in Vivo Models

Jennifer A. Juno, Kathleen M. Wragg, Anne B. Kristensen, Wen Shi Lee, Kevin J. Selva, Renee M. Van Der Sluis, Anthony D. Kelleher, Benjamin R. Bavinton, Andrew E. Grulich, Sharon R. Lewin, Stephen J. Kent, Matthew S. Parsons

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that 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 h of SP exposure (P 0.03). Meanwhile, NK cells retain the capacity to produce limited amounts of MIP-1/MIP-1 in response to anti-HIV-1 antibody-dependent stimulation (median, 9.5% MIP-1 and/or MIP-1), 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 of the 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.

Original languageEnglish
Article numbere0024219
Number of pages16
JournalJournal of Virology
Volume93
Issue number11
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • CCR5
  • Chemokines
  • HIV
  • Nonhuman primate
  • RANTES
  • Semen
  • Seminal plasma
  • T cells

Cite this

Juno, J. A., Wragg, K. M., Kristensen, A. B., Lee, W. S., Selva, K. J., Van Der Sluis, R. M., ... Parsons, M. S. (2019). Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of in Vitro versus in Vivo Models. Journal of Virology, 93(11), [e0024219]. https://doi.org/10.1128/JVI.00242-19
Juno, Jennifer A. ; Wragg, Kathleen M. ; Kristensen, Anne B. ; Lee, Wen Shi ; Selva, Kevin J. ; Van Der Sluis, Renee M. ; Kelleher, Anthony D. ; Bavinton, Benjamin R. ; Grulich, Andrew E. ; Lewin, Sharon R. ; Kent, Stephen J. ; Parsons, Matthew S. / Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of in Vitro versus in Vivo Models. In: Journal of Virology. 2019 ; Vol. 93, No. 11.
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abstract = "Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that 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 h of SP exposure (P 0.03). Meanwhile, NK cells retain the capacity to produce limited amounts of MIP-1/MIP-1 in response to anti-HIV-1 antibody-dependent stimulation (median, 9.5{\%} MIP-1 and/or MIP-1), 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 of the 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.",
keywords = "CCR5, Chemokines, HIV, Nonhuman primate, RANTES, Semen, Seminal plasma, T cells",
author = "Juno, {Jennifer A.} and Wragg, {Kathleen M.} and Kristensen, {Anne B.} and Lee, {Wen Shi} and Selva, {Kevin J.} and {Van Der Sluis}, {Renee M.} and Kelleher, {Anthony D.} and Bavinton, {Benjamin R.} and Grulich, {Andrew E.} and Lewin, {Sharon R.} and Kent, {Stephen J.} and Parsons, {Matthew S.}",
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Juno, JA, Wragg, KM, Kristensen, AB, Lee, WS, Selva, KJ, Van Der Sluis, RM, Kelleher, AD, Bavinton, BR, Grulich, AE, Lewin, SR, Kent, SJ & Parsons, MS 2019, 'Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of in Vitro versus in Vivo Models', Journal of Virology, vol. 93, no. 11, e0024219. https://doi.org/10.1128/JVI.00242-19

Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of in Vitro versus in Vivo Models. / Juno, Jennifer A.; Wragg, Kathleen M.; Kristensen, Anne B.; Lee, Wen Shi; Selva, Kevin J.; Van Der Sluis, Renee M.; Kelleher, Anthony D.; Bavinton, Benjamin R.; Grulich, Andrew E.; Lewin, Sharon R.; Kent, Stephen J.; Parsons, Matthew S.

In: Journal of Virology, Vol. 93, No. 11, e0024219, 01.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Juno, Jennifer A.

AU - Wragg, Kathleen M.

AU - Kristensen, Anne B.

AU - Lee, Wen Shi

AU - Selva, Kevin J.

AU - Van Der Sluis, Renee M.

AU - Kelleher, Anthony D.

AU - Bavinton, Benjamin R.

AU - Grulich, Andrew E.

AU - Lewin, Sharon R.

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AU - Parsons, Matthew S.

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N2 - Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that 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 h of SP exposure (P 0.03). Meanwhile, NK cells retain the capacity to produce limited amounts of MIP-1/MIP-1 in response to anti-HIV-1 antibody-dependent stimulation (median, 9.5% MIP-1 and/or MIP-1), 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 of the 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.

AB - Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that 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 h of SP exposure (P 0.03). Meanwhile, NK cells retain the capacity to produce limited amounts of MIP-1/MIP-1 in response to anti-HIV-1 antibody-dependent stimulation (median, 9.5% MIP-1 and/or MIP-1), 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 of the 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.

KW - CCR5

KW - Chemokines

KW - HIV

KW - Nonhuman primate

KW - RANTES

KW - Semen

KW - Seminal plasma

KW - T cells

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