Breakthrough brings Temple researchers and their collaborators closer to a cure for human HIV infection
From
Temple University
November
30, 2020 -- Taking a major step forward in HIV research, scientists at
the Lewis Katz
School of Medicine at Temple University have successfully edited SIV –
a virus closely related to HIV, the
cause of AIDS – from the genomes of non-human primates. The breakthrough brings
Temple researchers and their collaborators closer than ever to developing a
cure for human HIV infection.
“We show for the first time that a
single inoculation of our CRISPR gene-editing construct, carried by an
adeno-associated virus, can edit out the SIV genome from infected cells in
rhesus macaque monkeys,” said Kamel Khalili,
PhD, Laura H. Carnell Professor and Chair of the Department of
Neuroscience, Director of the Center for Neurovirology, and Director of the Comprehensive
NeuroAIDS Center at the Lewis Katz School of Medicine at Temple University
(LKSOM).
Dr. Khalili was a senior co-investigator
on the new study, with Tricia H. Burdo, PhD, Associate Professor and Associate
Chair of Education in the Department of Neuroscience at LKSOM, who is an expert
on the utilization of the SIV (simian immunodeficiency virus)-infected
antiretroviral therapy (ART)-treated rhesus macaque model for HIV pathogenesis
and cure studies; and with Andrew G. MacLean, PhD, Associate Professor at the Tulane
National Primate Research Center and the Department of Microbiology and
Immunology at Tulane University School of Medicine, and Binhua
Ling, PhD, Associate Professor at the Southwest National Primate Research
Center, Texas Biomedical Research Institute. Dr. Ling was previously Associate
Professor at the Tulane National Primate Research Center and the Department of
Microbiology and Immunology at Tulane University School of Medicine. Pietro
Mancuso, PhD, an Assistant Scientist in Dr. Khalili's laboratory in the
Department of Neuroscience at LKSOM, was first author on the report, which
was published online November 27 in the journal Nature
Communications.
Of particular significance, the new work
shows that the gene-editing construct developed by Dr. Khalili's team can reach
infected cells and tissues known to be viral reservoirs for SIV and HIV. These
reservoirs, which are cells and tissues where the viruses integrate into host
DNA and hide away for years, are a major barrier to curing infection. SIV or
HIV in these reservoirs lies beyond the reach of ART, which suppresses viral
replication and clears the virus from the blood. As soon as ART is stopped, the
viruses emerge from their reservoirs and renew replication.
In non-human primates, SIV behaves very
much like HIV. “The SIV-infected rhesus macaque model studied in Dr. Burdo's
lab is an ideal large animal model for recapitulating HIV infection in humans,”
explained Dr. Khalili.
For
the new study, the researchers began by designing an SIV-specific CRISPR-Cas9
gene-editing construct. Experiments in cell culture confirmed that the editing
tool cleaved integrated SIV DNA at the correct location from host cell DNA,
with limited risk of potentially harmful gene editing at off-target sites. The
research team then packaged the construct into an adeno-associated virus 9
(AAV9) carrier, which could be injected intravenously into SIV-infected
animals.
Dr.
Burdo, in collaboration with colleagues at Tulane National Primate Research
Center, randomly selected three SIV-infected macaques to each receive a single
infusion of AAV9-CRISPR-Cas9, with another animal serving as a control. After
three weeks, the researchers harvested blood and tissues from the animals.
Analyses showed that in AAV9-CRISPR-Cas9-treated macaques, the gene-editing
construct had been distributed to a broad range of tissues, including the bone
marrow, lymph nodes, and spleen, and had reached CD4+ T cells, which are a
significant viral reservoir.
Moreover,
the Temple researchers demonstrated that the SIV genome was effectively cleaved
from infected cells, based on genetic analyses of tissues from treated animals.
“The step-by-step excision of SIV DNA occurred with high efficiency from
tissues and blood cells,” Dr. Mancuso explained. Excision efficiency varied by
tissue but reached notably high levels in the lymph nodes.
The
new study is a continuation of efforts by Dr. Khalili and colleagues to develop
a novel gene-editing system using CRISPR-Cas9 technology – the subject of the
2020 Nobel Prize in Chemistry – to specifically remove HIV DNA from genomes
harboring the virus. The researchers have shown previously that their system can
effectively eliminate HIV DNA from cells and tissues in HIV-infected small
animal models, including HIV-1 humanized mice.
Co-corresponding
author Dr. MacLean is encouraged by the findings. “This is an important
development in what we hope will be an end to HIV/AIDS,” says MacLean. “The
next step is to evaluate this treatment over a longer period of time to
determine if we can achieve complete elimination of the virus, possibly even
taking subjects off of ART.”
Dr.
MacLean is hopeful that this treatment strategy will translate to the human
population. The biotech company Excision BioTherapeutics, of which Dr. Khalili
is a scientific founder and where Dr. Burdo contributes to preclinical research
and development and serves on the Scientific Advisory Board, will assist with
funding and infrastructure for larger scale studies and future clinical trials
after approval by the Food and Drug Administration.
“We
hope to soon move our work into clinical studies in humans as well,” Dr.
Khalili added. “People worldwide have been suffering with HIV for 40 years, and
we are now very near to clinical research that could lead to a cure for HIV
infection.”
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