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Kamel Khalili, Ph.D.Laura H. Carnell Professor and Chair
Department of Neuroscience
Director
Center for Neurovirology &
Comprehensive NeuroAIDS Center
Co-Director, Center for Translational AIDS Research
Lewis Katz School of Medicine at Temple University
Philadelphia, Pennsylvania
Gene Editing Strategy for Eliminating
HIV-1/AIDS
Workshop on HIV&Aging
September 2016
The Aging Face of AIDS
cART
Neurocognitive disorders
Depression
Cardiomyopathy
Dislipidemia
Renal Disease
Other comorbidities
In vivo editing of HIV-1 by CRISPR:
small animal models
• Tg26 transgenic mice
transgenic mice containing entire HIV pNL4-3 (partial Dgag/pol)
HIV transgenic rats
transgenic mice containing entire HIV pNL4-3 (partial Dgag/pol)
• EcoHIV infected mice
chimeric HIV containing MuLV envelope and Luciferase reporter –
virus is replication competent in mice
• BLT humanized mice
circulating human-derived PBMCs – supports HIV replication in vivo
Intraperiotoneal Infection of BLT Mice
with HIV-NL-BAL-eLuc
Dorsal D2 p.i. D5 p.i. D7 p.i. D14 p.i.Ventral
3.1 X 104 TCIU
D21 p.i. D28 p.i.
Kidney
Lung
Liver
Human thymic
organoidSpleen
Kinetics of Infection
A
B
B7M2 Mice Intraperiotoneally Inoculated
With HIV-BAL-eLuc
D86D65
D16 D22 D30 D37
D44
D2
D52
1 x 106 TCIU
AAV-Cas9 (IV)
B10M4 Intraperitoneally Inoculated
with HIV-BaL-eLuc(1x105 TCIU)
D3 p.i. D7 p.i. D14 p.i. D21 p.i.
ART (TFV/FTC/RAL)
D28 p.i. / D5 p.a D35 p.i. / D12 p.a D63 p.i. / D25 p.w.
HIV rebound
D42 p.i. / D4 p.a
ART Withdrawal
p.i., Post-inoculation; p.a., Post-antiretroviral therapy (ART); p.w., Post-withdrawal of ART
Acknowledgments
Supported by grants awarded by NIH to KK, BW, JK, RB, and HG.
Infrastructure support: Comprehensive NeuroAIDS Center (CNAC)
Funded by NIMH (P30MH092177)
Temple University (KSOM)
Rafal Kaminski, Ph.D.
Hassen Wollebo, Ph.D.
Yilan Chen, M.D., Ph.D.
Wenhui Hu, M.D., Ph.D.
Chaoran Yin, M.D.
Fang Li
Yonggang Zhang, M.D., Ph.D.
Tracy Fischer, Ph.D.
Ellen Tedaldi, M.D.
Jeffrey Jacobson, M.D.
Julian Salkind
Ramona Bella
Pasquale Ferrante
(University of Milan)
Drexel University (DUCOM)
Brian Wigdahl, Ph.D.
and his team
George Mason University
Fatah Kashanchi, Ph.D.
and his team
Florida International University
Madhavan Nair, Ph.D.
and his team.
University of Nebraska (UNMC)
Howard Gendelman, M.D.
and his team
Case Western Reserve
University (CWRU)
Jonathan Karn, Ph.D.
and his team
University of South Carolina
Rosemarie Booze, Ph.D.
and her team
Disclosures
Kamel Khalili is a board member, scientific advisor, and holds equity in Excision
Biotherapeutics, a biotech start-up who has licensed the viral gene editing technology
from Temple University for commercial development and clinical trials.
Funding