BIRC2/cIAP1 Is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency.
Combination antiretroviral therapy (ART) is able to suppress HIV-1 replication to undetectable levels. However, the persistence of latent viral reservoirs allows for a rebound of viral load upon cessation of therapy. Thus, therapeutic strategies to eradicate the viral latent reservoir are critically needed. Employing a targeted RNAi screen, we identified the ubiquitin ligase BIRC2 (cIAP1), a repressor of the noncanonical NF-κB pathway, as a potent negative regulator of LTR-dependent HIV-1 transcription. Depletion of BIRC2 through treatment with small molecule antagonists known as Smac mimetics enhanced HIV-1 transcription, leading to a reversal of latency in a JLat latency model system. Critically, treatment of resting CD4+ T cells isolated from ART-suppressed patients with the histone deacetylase inhibitor (HDACi) panobinostat together with Smac mimetics resulted in synergistic activation of the latent reservoir. These data implicate Smac mimetics as useful agents for shock-and-kill strategies to eliminate the latent HIV reservoir.
Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Lars
L
Pache
Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Miriam S
MS
Dutra
Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East #2100, Salt Lake City, UT 84112, USA.
Adam M
AM
Spivak
Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
John M
JM
Marlett
Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Jeffrey P
JP
Murry
Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Young
Y
Hwang
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ana M
AM
Maestre
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Lara
L
Manganaro
Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Mitchell
M
Vamos
Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Peter
P
Teriete
Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East #2100, Salt Lake City, UT 84112, USA.
Laura J
LJ
Martins
Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany; German Center for Infection Research (DZIF), 63225 Langen, Germany.
Renate
R
König
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Viviana
V
Simon
Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East #2100, Salt Lake City, UT 84112, USA.
Alberto
A
Bosque
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ana
A
Fernandez-Sesma
Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nicholas D P
ND
Cosford
Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Frederic D
FD
Bushman
Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
John A T
JA
Young
Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East #2100, Salt Lake City, UT 84112, USA.
Vicente
V
Planelles
Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: schanda@sbpdiscovery.org.
Sumit K
SK
Chanda
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D000077767:Panobinostat; D014158:Transcription, Genetic / Q000187:drug effects*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
D006877:Hydroxamic Acids; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; C532637:SMAC peptide; D000077767:Panobinostat; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases