PMID- 28904191
OWN - NLM
STAT- MEDLINE
DCOM- 20171102
LR  - 20180406
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 91
IP  - 22
DP  - 2017 Nov 15
TI  - Dose of Retroviral Infection Determines Induction of Antiviral NK Cell Responses.
LID - e01122-17 [pii]
LID - 10.1128/JVI.01122-17 [doi]
AB  - Natural killer (NK) cells are part of the innate immune system and recognize
      virus-infected cells as well as tumor cells. Conflicting data about the
      beneficial or even detrimental role of NK cells in different infectious diseases 
      have been described previously. While the type of pathogen strongly influences NK
      cell functionality, less is known about how the infection dose influences the
      quality of a NK cell response against retroviruses. In this study, we used the
      well-established Friend retrovirus (FV) mouse model to investigate the impact of 
      virus dose on the induction of antiviral NK cell functions. High-dose virus
      inoculation increased initial virus replication compared to that with medium- or 
      low-dose viral challenge and significantly improved NK cell activation. Antiviral
      NK cell activity, including in vivo cytotoxicity toward infected target cells,
      was also enhanced by high-dose virus infection. NK cell activation following
      high-dose viral challenge was likely mediated by activated dendritic cells (DCs) 
      and macrophages and the NK cell-stimulating cytokines interleukin 15 (IL-15) and 
      IL-18. Neutralization of these cytokines decreased NK cell functions and
      increased viral loads, whereas IL-15 and IL-18 therapy improved NK cell activity.
      Here we demonstrate that virus dose positively correlates with antiviral NK cell 
      activity and function, which are at least partly driven by IL-15 and IL-18. Our
      results suggest that NK cell activity may be therapeutically enhanced by
      administering IL-15 and IL-18 in virus infections that inadequately activate NK
      cells.IMPORTANCE In infections with retroviruses, like HIV and FV infection of
      mice, NK cells clearly mediate antiviral activities, but they are usually not
      sufficient to prevent severe pathology. Here we show that the initial infection
      dose impacts the induction of an antiviral NK cell response during an acute
      retroviral infection, which had not investigated before. High-dose infection
      resulted in a strong NK cell functionality, whereas no antiviral activities were 
      detected after low- or medium-dose infection. Interestingly, DCs and macrophages 
      were highly activated after high-dose FV challenge, which corresponded with
      increased levels of NK cell-stimulating cytokines IL-15 and IL-18. IL-15 and
      IL-18 neutralization decreased NK cell functions, whereas IL-15 and IL-18 therapy
      improved NK cell activity. Here we show the importance of cytokines for NK cell
      activation in retroviral infections; our findings suggest that immunotherapy
      combining the well-tolerated cytokines IL-15 and IL-18 might be an interesting
      approach for antiretroviral treatment.
CI  - Copyright (c) 2017 Littwitz-Salomon et al.
FAU - Littwitz-Salomon, Elisabeth
AU  - Littwitz-Salomon E
AD  - Institute for Virology of the University Hospital Essen, University of
      Duisburg-Essen, Essen, Germany Elisabeth.Littwitz@uni-due.de.
FAU - Schimmer, Simone
AU  - Schimmer S
AD  - Institute for Virology of the University Hospital Essen, University of
      Duisburg-Essen, Essen, Germany.
FAU - Dittmer, Ulf
AU  - Dittmer U
AD  - Institute for Virology of the University Hospital Essen, University of
      Duisburg-Essen, Essen, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171027
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Interleukin-15)
RN  - 0 (Interleukin-18)
SB  - IM
MH  - Animals
MH  - Dose-Response Relationship, Immunologic
MH  - Female
MH  - Friend murine leukemia virus/*immunology
MH  - Interleukin-15/immunology/pharmacology
MH  - Interleukin-18/immunology/pharmacology
MH  - Killer Cells, Natural/*immunology
MH  - *Lymphocyte Activation
MH  - Mice
MH  - Retroviridae Infections/drug therapy/*immunology
PMC - PMC5660477
OTO - NOTNLM
OT  - *Friend retrovirus
OT  - *antiviral activity
OT  - *interleukins
OT  - *natural killer cells
OT  - *virus dose
EDAT- 2017/09/15 06:00
MHDA- 2017/11/03 06:00
CRDT- 2017/09/15 06:00
PHST- 2017/07/03 00:00 [received]
PHST- 2017/09/01 00:00 [accepted]
PHST- 2017/09/15 06:00 [pubmed]
PHST- 2017/11/03 06:00 [medline]
PHST- 2017/09/15 06:00 [entrez]
AID - JVI.01122-17 [pii]
AID - 10.1128/JVI.01122-17 [doi]
PST - epublish
SO  - J Virol. 2017 Oct 27;91(22). pii: JVI.01122-17. doi: 10.1128/JVI.01122-17. Print 
      2017 Nov 15.