Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors
Publication Date
December 21, 2017
Authors
Christina Gavegnano, Jessica H. Brehm, Franck P. Dupuy, Aarthi Talla, et al
Volume
13
Issue
12
Pages
e1006740
DOI
https://dx.plos.org/10.1371/journal.ppat.1006740
Publisher URL
http://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1006740
Scopus
85039904394
Mendeley
http://www.mendeley.com/research/novel-mechanisms-inhibit-hiv-reservoir-seeding-using-jak-inhibitors
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Mendeley | Further Information

{"title"=>"Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors", "type"=>"journal", "authors"=>[{"first_name"=>"Christina", "last_name"=>"Gavegnano", "scopus_author_id"=>"35145674200"}, {"first_name"=>"Jessica H.", "last_name"=>"Brehm", "scopus_author_id"=>"17343449600"}, {"first_name"=>"Franck P.", "last_name"=>"Dupuy", "scopus_author_id"=>"8940648000"}, {"first_name"=>"Aarthi", "last_name"=>"Talla", "scopus_author_id"=>"57045855100"}, {"first_name"=>"Susan Pereira", "last_name"=>"Ribeiro", "scopus_author_id"=>"24492453800"}, {"first_name"=>"Deanna A.", "last_name"=>"Kulpa", "scopus_author_id"=>"6507075670"}, {"first_name"=>"Cheryl", "last_name"=>"Cameron", "scopus_author_id"=>"57196652647"}, {"first_name"=>"Stephanie", "last_name"=>"Santos", "scopus_author_id"=>"57200141994"}, {"first_name"=>"Selwyn J.", "last_name"=>"Hurwitz", "scopus_author_id"=>"7101862038"}, {"first_name"=>"Vincent C.", "last_name"=>"Marconi", "scopus_author_id"=>"22951187600"}, {"first_name"=>"Jean Pierre", "last_name"=>"Routy", "scopus_author_id"=>"7003631689"}, {"first_name"=>"Laurent", "last_name"=>"Sabbagh", "scopus_author_id"=>"15519626600"}, {"first_name"=>"Raymond F.", "last_name"=>"Schinazi", "scopus_author_id"=>"36049673200"}, {"first_name"=>"Rafick Pierre", "last_name"=>"Sékaly", "scopus_author_id"=>"7103324485"}], "year"=>2017, "source"=>"PLoS Pathogens", "identifiers"=>{"scopus"=>"2-s2.0-85039904394", "sgr"=>"85039904394", "doi"=>"10.1371/journal.ppat.1006740", "pui"=>"620067270", "pmid"=>"29267399", "isbn"=>"1111111111", "issn"=>"15537374"}, "id"=>"8e7a4595-cb35-3347-84bc-b6add19a9d91", "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.", "link"=>"http://www.mendeley.com/research/novel-mechanisms-inhibit-hiv-reservoir-seeding-using-jak-inhibitors", "reader_count"=>13, "reader_count_by_academic_status"=>{"Librarian"=>1, "Student > Doctoral Student"=>2, "Researcher"=>3, "Student > Ph. D. Student"=>3, "Student > Bachelor"=>2, "Student > Master"=>1, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Librarian"=>1, "Student > Doctoral Student"=>2, "Researcher"=>3, "Student > Ph. D. Student"=>3, "Student > Bachelor"=>2, "Student > Master"=>1, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>5, "Arts and Humanities"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "group_count"=>1}

Scopus | Further Information

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