PMID- 34281386
OWN - NLM
STAT- MEDLINE
DCOM- 20211231
LR  - 20220519
IS  - 2150-7511 (Electronic)
VI  - 12
IP  - 4
DP  - 2021 Aug 31
TI  - Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 
      1 Reactivation.
PG  - e0117621
LID - 10.1128/mBio.01176-21 [doi]
LID - e01176-21
AB  - We previously reported that herpes simplex virus 1 (HSV-1) ICP22 binds to CD80 
      and suppresses CD80 expression in vitro and in vivo. Similar to ICP22, the 
      cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In 
      this study, we asked whether, similar to ICP22-null virus, the absence of these 
      costimulatory molecules will reduce HSV-1 infectivity. To test our hypothesis, 
      CD28(-/-), CD28(-/-) CTLA4(-/-), PD-L1(-/-), and wild-type control BALB/c mice 
      were ocularly infected with HSV-1 strain KOS. Levels of virus replication in the 
      eye, corneal scarring (CS), latency, and reactivation in infected mice were 
      determined. Expression of different genes in the trigeminal ganglia (TG) of 
      latently infected mice was also determined by NanoString and quantitative reverse 
      transcription-PCR (qRT-PCR). In the absence of costimulatory molecules, latency 
      levels were higher than those in wild-type control mice, but despite higher 
      latency, a significant number of TG from infected knockout mice did not 
      reactivate. Reduced reactivation correlated with downregulation of 26 similar 
      cellular genes that are associated with inflammatory signaling and innate immune 
      responses. These results suggest that lower reactivation directly correlates with 
      lower expression of interferon signaling. Thus, despite having different modes of 
      actions, we identified a similar function for CD28, CTLA4, and PD-L1 in HSV-1 
      reactivation that is dependent on their interactions with CD80. Therefore, 
      blocking these interactions could be a therapeutic target for HSV-1-induced 
      reactivation. IMPORTANCE Costimulatory molecules play an important role in 
      activation of T cell responses, and T cells contribute to HSV-1-induced eye 
      disease in the host. Similar to HSV-1 ICP22, the cellular costimulatory molecules 
      CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we have shown that the 
      absence of these costimulatory molecules significantly reduced HSV-1 ex vivo 
      reactivation. Therefore, inhibiting the binding of costimulatory molecules to 
      CD80 could be used to reduce reactivation and, consequently, HSV-1-induced eye 
      disease.
FAU - Matundan, Harry H
AU  - Matundan HH
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los 
      Angeles, California, USA.
FAU - Jaggi, Ujjaldeep
AU  - Jaggi U
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los 
      Angeles, California, USA.
FAU - Yu, Jack
AU  - Yu J
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los 
      Angeles, California, USA.
FAU - Akbari, Omid
AU  - Akbari O
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, California, USA.
FAU - Ghiasi, Homayon
AU  - Ghiasi H
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los 
      Angeles, California, USA.
LA  - eng
GR  - R01 HL144790/HL/NHLBI NIH HHS/United States
GR  - R01 EY029160/EY/NEI NIH HHS/United States
GR  - R01 EY024649/EY/NEI NIH HHS/United States
GR  - R01 HL151493/HL/NHLBI NIH HHS/United States
GR  - R01 EY026944/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210720
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD28 Antigens)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Cd274 protein, mouse)
RN  - 0 (Ctla4 protein, mouse)
SB  - IM
MH  - Animals
MH  - B7-H1 Antigen/*genetics
MH  - CD28 Antigens/*genetics
MH  - CTLA-4 Antigen/*genetics
MH  - Eye/virology
MH  - Female
MH  - Herpes Simplex/virology
MH  - Herpesvirus 1, Human/genetics/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - Trigeminal Ganglion/virology
MH  - Virus Activation/*genetics
MH  - Virus Latency
MH  - Virus Replication/genetics
PMC - PMC8406230
OTO - NOTNLM
OT  - HSV-1
OT  - antigen-presenting cells
OT  - corneal scarring
OT  - knockout
OT  - latency
OT  - ocular infection
OT  - reactivation
EDAT- 2021/07/21 06:00
MHDA- 2022/01/01 06:00
PMCR- 2021/07/20
CRDT- 2021/07/20 05:27
PHST- 2021/07/21 06:00 [pubmed]
PHST- 2022/01/01 06:00 [medline]
PHST- 2021/07/20 05:27 [entrez]
PHST- 2021/07/20 00:00 [pmc-release]
AID - mBio01176-21 [pii]
AID - 10.1128/mBio.01176-21 [doi]
PST - ppublish
SO  - mBio. 2021 Aug 31;12(4):e0117621. doi: 10.1128/mBio.01176-21. Epub 2021 Jul 20.