Gene Therapy for HIV and Chronic Infections

246 Pages·2015·5.484 MB·English

by  Ben Berkhout, Hildegund C.J. Ertl, Marc S. Weinberg (eds.)

Advances in Experimental Medicine and Biology 848
American Society of Gene & Cell Therapy
Ben Berkhout
Hildegund C.J. Ertl
Marc S. Weinberg
Editors
Gene Therapy
for HIV and
Chronic Infections
Advances in Experimental Medicine and Biology
American Society of Gene & Cell Therapy
Guangping Gao, University of Massachusetts Medical School,
Worcester, MA, USA
Dirk Grimm, University of Heidelberg,
Heidelberg, Germany
Volume 848
Editorial Board:
IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
More information about this series at h ttp://www.springer.com/series/5584

Ben Berkhout (cid:129) Hildegund C.J. Ertl
Marc S. Weinberg
Editors
Gene Therapy for HIV
and Chronic Infections
Editors
Ben Berkhout Hildegund C.J. Ertl
University of Amsterdam The Wistar Institute
Amsterdam , The Netherlands University of Pennsylvania
Philadelphia , PA , USA
Marc S. Weinberg
University of the Witwatersrand
Johannesburg , South Africa
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-1-4939-2431-8 ISBN 978-1-4939-2432-5 (eBook)
DOI 10.1007/978-1-4939-2432-5
Library of Congress Control Number: 2015932964
Springer New York Heidelberg Dordrecht London
© American Society of Gene and Cell Therapy 2015
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Pref ace
T his book volume deals with gene therapy and gene transfer approaches to prevent
or treat chronic virus infections. The focus of many chapters is on the Big Three:
human immunodefi ciency virus (HIV)-1, hepatitis B virus (HBV), and hepatitis C
virus (HCV). HIV continues to be a major global public health concern, having
claimed more than 25 million lives due to AIDS over the past three decades. In
2013, there were approximately 35 million people living with HIV. Sub-Saharan
Africa is the most affected region, with nearly one carrier in every 20 adults.
According to the World Health Organization (WHO), two billion persons (approxi-
mately 5 % of the world’s population) have been infected with HBV, of which more
than 350 million have a chronic HBV infection. It has been estimated that up to 3 %
of the world’s population is infected with HCV, of which 170 million people are
chronically infected, and an additional three to four million people are newly
infected each year. Long-term chronic infection with one or both of these hepatitis
viruses is the most common cause of liver fi brosis and cirrhosis, leading to liver
failure and hepatocellular carcinoma.
There is no cure for HIV infection, but effective treatment with antiretroviral
drugs has dramatically improved the life span and quality of life of infected indi-
viduals. A similar trend can already be recognized for HBV and HCV: the devel-
opment of multiple (directly acting) antiviral drugs and plans to control or even
cure the infection. However, approaches that help prevent infection or which pro-
vide long-lasting treatment (such as a cure) remain important clinical goals. Gene
therapy can theoretically provide a means to obtain durable virus suppression in
the absence of medication.
G ene therapy applications for clearance of chronic virus infections have been
discussed since the early 1990s. In case of persisting infections with CMV, a herpes
virus, vaccination such as with a DNA vaccine has shown to lower viremia, which
may be benefi cial to reduce CMV-mediated disease prior to immunosuppression of
transplant recipients. Whereas a true cure seems diffi cult to achieve for HIV due to
its intrinsic property to deposit its genome into that of the host, such attempts may
be within reach for HCV where spontaneous viral clearance occurs in a small per-
centage of the infected individuals. But even the more diffi cult HIV scenario has
v
vi Preface
recently been spurred by the fi rst (and thus far only) functional cure reported for the
“Berlin HIV patient.” In this unique case, a bone marrow transplant was performed
because of leukemia and the selection of a CCR5-negative donor, whose cells lack
expression of the major coreceptor used by HIV for cell entry, has resulted in the
apparent disappearance of the virus from blood. It is clear that such a transplant
remains a high-risk procedure, but it provides an important proof of principle that
could hopefully be mimicked by gene therapy approaches.
A diversity of anti-HIV gene therapies have been proposed and several of these
strategies also hold potential for anti-HBV or anti-HCV approaches. In Chap. 6 by
Cornu et al., the multitude of editing approaches against the CCR5 target suggests a
very positive pipeline of options for anti-HIV gene therapy. There are alternative
ways to reach the same end point by, for example, silencing of CCR5 expression
posttranscriptionally or ablating its expression by targeting the CCR5 genomic
locus for excision or epigenetic shutdown. Herrera Carrillo and Berkhout (Chap. 4 )
discuss RNA interference (RNAi)-mediated gene silencing approaches against HIV,
thereby targeting either host cell cofactors or the viral RNA genome. The particular
focus is on combinatorial RNAi strategies to prevent viral escape. Takahashi et al.
(Chap. 1 1 ) describe how siRNAs targeted to HIV targets as well as to host genes can
be delivered by cell-internalizing aptamers, a strategy that represents a novel cell-
specifi c delivery method, allowing systemic application of naked RNA to infected
patients. Scarborough and Gatignol (Chap. 5 ) describe ribozymes, catalytic RNA
molecules and conjugates thereof with other inhibitory moieties. Ribozymes can be
designed in a sequence-specifi c manner to cleave other RNA molecules, e.g., the
HIV-1 RNA genome. Egerer et al. (Chap. 1 0) describe the conversion of known
antiviral peptide drugs that block the membrane fusion process into transgene con-
structs that express potent antiviral proteins, either on the cell surface or in a secreted
form. Blazquez and Fortes (Chap. 3 ) describe the unique antiviral properties of the
modifi ed U1 small nuclear ribonucleoprotein (snRNP), which is particularly suited
for applications against HIV and HBV whose viral genomes express mRNAs that
must be polyadenylated.
Verstegen et al. (Chap. 1 ) focus on the history of anti-HCV therapeutics, from
interferon to directly acting antiviral drugs and the prospects for gene therapeutic
strategies. The prospects of a gene therapy for HBV are described by Bloom et al.
(Chap. 2 ). Wu et al. (Chap. 7 ) deals with CMV that infects up to 60–95 % of adults.
Although primary infections are in general benign, CMV establishes a latent infec-
tion and has been linked to fatal disease in immunocompromised patients and to
chronic disease such as infl ammatory diseases, cancer, and heart diseases in indi-
viduals with an intact immune system.
Prophylactic vaccines are not yet available for HIV, HCV, or CMV and correlates
of protection remain ill-defi ned. For HIV it is assumed that virus-neutralizing anti-
bodies may prevent virus acquisition. Nevertheless, as the envelope of HIV-1, the
target for neutralizing antibodies is extremely variable, immunogens that elicit
those that are broadly cross-reactive remain elusive. Schnepp and Johnson (Chap. 8 )
describe an alternative genetic vaccination approach by intramuscular gene transfer
Preface vii
of adeno-associated virus vectors encoding an HIV-1-specifi c broadly neutralizing
antibody for prevention of infection.
More recently a lot of attention has been placed on the role and importance of
noncoding RNAs (ncRNAs) in viral infections, especially with regard to the mainte-
nance of cellular transcriptional regulation. Saayman et al. (Chap. 9 ) discuss the role
of viral and cellular ncRNAs with respect to strategies aimed at affecting HIV latency.
M ost early results have been described in appropriate in vitro models, but some
studies have progressed towards preclinical animal models and a few antiviral gene
therapies have progressed towards clinical trials. This book provides a thorough
overview of this rapidly progressing fi eld.
Amsterdam, The Netherlands Ben Berkhout
Philadelphia, PA, USA Hildegund C. J. Ertl
Johannesburg, South Africa Marc S. Weinberg

Contents
Gene Therapies for Hepatitis C Virus ........................................................... 1
Monique M. A. Verstegen , Qiuwei Pan , and Luc J. W. van der Laan
Recent Advances in Use of Gene Therapy to Treat Hepatitis B
Virus Infection ................................................................................................. 31
Kristie Bloom , Abdullah Ely , and Patrick Arbuthnot
U1 interference (U1i) for Antiviral Approaches ........................................... 51
Lorea Blázquez and Puri Fortes
Gene Therapy Strategies to Block HIV-1 Replication
by RNA Interference ....................................................................................... 71
Elena Herrera-Carrillo and Ben Berkhout
HIV and Ribozymes ........................................................................................ 97
Robert J. Scarborough and Anne Gatignol
Editing CCR5: A Novel Approach to HIV Gene Therapy ........................... 117
Tatjana I. Cornu , Claudio Mussolino , Kristie Bloom , and Toni Cathomen
Synthetic DNA Approach to Cytomegalovirus
Vaccine/Immune Therapy .............................................................................. 131
Stephan J. Wu , Daniel O. Villarreal , Devon J. Shedlock ,
and David B. Weiner
Vector-Mediated Antibody Gene Transfer for Infectious Diseases ............ 149
Bruce C. Schnepp and Philip R. Johnson
HIV Latency and the Noncoding RNA Therapeutic Landscape ................ 169
Sheena Saayman , Thomas C. Roberts , Kevin V. Morris ,
and Marc S. Weinberg
ix