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Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.

Abstract Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15)-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15) ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos pathogens
Publication Year Start




PMID- 29267399
OWN - NLM
STAT- MEDLINE
DCOM- 20180102
LR  - 20180111
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Linking)
VI  - 13
IP  - 12
DP  - 2017 Dec
TI  - Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.
PG  - e1006740
LID - 10.1371/journal.ppat.1006740 [doi]
AB  - Despite advances in the treatment of HIV infection with ART, elucidating
      strategies to overcome HIV persistence, including blockade of viral reservoir
      establishment, maintenance, and expansion, remains a challenge. T cell
      homeostasis is a major driver of HIV persistence. Cytokines involved in
      regulating homeostasis of memory T cells, the major hub of the HIV reservoir,
      trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and
      ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of
      the HIV reservoir in vitro. We provide direct demonstration for involvement of
      the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5
      strongly correlates with increased levels of integrated viral DNA in vivo, and in
      vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated
      HIV DNA. We show that Jak inhibitors block viral production from infected cells, 
      inhibit gamma-C receptor cytokine (IL-15)-induced viral reactivation from latent 
      stores thereby preventing transmission of infectious particles to bystander
      activated T cells. These results show that dysregulation of the Jak-STAT pathway 
      is associated with viral persistence in vivo, and that Jak inhibitors target key 
      events downstream of gamma-C cytokine (IL-2, IL-7 and IL-15) ligation to their
      receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell 
      subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to 
      prevent key events of T cell activation that regulate HIV persistence and
      together, specific, potent blockade of these events may be integrated to future
      curative strategies.
FAU - Gavegnano, Christina
AU  - Gavegnano C
AD  - Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of
      Pediatrics, Emory University, Atlanta, GA, United States of America.
FAU - Brehm, Jessica H
AU  - Brehm JH
AD  - Case Western Reserve University, Dept. of Pathology, Cleveland, OH, United States
      of America.
FAU - Dupuy, Franck P
AU  - Dupuy FP
AD  - Research Institute of the MUHC, Montreal, QC, Canada.
FAU - Talla, Aarthi
AU  - Talla A
AD  - Case Western Reserve University, Dept. of Pathology, Cleveland, OH, United States
      of America.
FAU - Ribeiro, Susan Pereira
AU  - Ribeiro SP
AD  - Case Western Reserve University, Dept. of Pathology, Cleveland, OH, United States
      of America.
FAU - Kulpa, Deanna A
AU  - Kulpa DA
AD  - Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of
      Pediatrics, Emory University, Atlanta, GA, United States of America.
FAU - Cameron, Cheryl
AU  - Cameron C
AUID- ORCID: 0000-0002-0574-3781
AD  - Case Western Reserve University, Dept. of Pathology, Cleveland, OH, United States
      of America.
FAU - Santos, Stephanie
AU  - Santos S
AD  - Unconditional Love, Melbourne, FL, United States of America.
FAU - Hurwitz, Selwyn J
AU  - Hurwitz SJ
AD  - Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of
      Pediatrics, Emory University, Atlanta, GA, United States of America.
FAU - Marconi, Vincent C
AU  - Marconi VC
AUID- ORCID: 0000-0001-8409-4689
AD  - Division of Infectious Diseases, Emory University School of Medicine, Atlanta,
      GA, United States of America.
FAU - Routy, Jean-Pierre
AU  - Routy JP
AD  - Chronic Viral Illnesses Service Research Institute, Division of Hematology,
      McGill University Health Centre, Montreal, QC, Canada.
FAU - Sabbagh, Laurent
AU  - Sabbagh L
AUID- ORCID: 0000-0002-5097-4298
AD  - Universite de Montreal, Department of Microbiology, Infectiology, and Immunology,
      Montreal, QC, Canada.
FAU - Schinazi, Raymond F
AU  - Schinazi RF
AD  - Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of
      Pediatrics, Emory University, Atlanta, GA, United States of America.
FAU - Sekaly, Rafick Pierre
AU  - Sekaly RP
AUID- ORCID: 0000-0002-7816-4828
AD  - Case Western Reserve University, Dept. of Pathology, Cleveland, OH, United States
      of America.
LA  - eng
GR  - 1R01MH100999 /NH/NIH HHS/United States
GR  - 5P30AI050409 /NH/NIH HHS/United States
GR  - 5P01AI076174 /NH/NIH HHS/United States
GR  - 5U19AI096109 /NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171221
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Anti-HIV Agents)
RN  - 0 (INCB018424)
RN  - 0 (Janus Kinase Inhibitors)
RN  - 0 (Piperidines)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 87LA6FU830 (tofacitinib)
SB  - IM
MH  - Anti-HIV Agents/*pharmacology
MH  - CD4-Positive T-Lymphocytes/drug effects/*virology
MH  - Cells, Cultured
MH  - HIV Infections/*virology
MH  - HIV-1/drug effects/physiology
MH  - Humans
MH  - Janus Kinase Inhibitors/*pharmacology
MH  - Piperidines/pharmacology
MH  - Pyrazoles/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Pyrroles/pharmacology
MH  - Virus Latency/*drug effects
MH  - Virus Replication/drug effects
PMC - PMC5739511
EDAT- 2017/12/22 06:00
MHDA- 2018/01/03 06:00
CRDT- 2017/12/22 06:00
PHST- 2017/03/31 00:00 [received]
PHST- 2017/11/09 00:00 [accepted]
PHST- 2017/12/22 06:00 [entrez]
PHST- 2017/12/22 06:00 [pubmed]
PHST- 2018/01/03 06:00 [medline]
AID - 10.1371/journal.ppat.1006740 [doi]
AID - PPATHOGENS-D-17-00702 [pii]
PST - epublish
SO  - PLoS Pathog. 2017 Dec 21;13(12):e1006740. doi: 10.1371/journal.ppat.1006740.
      eCollection 2017 Dec.