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Accepted Manuscript: 10.1016/j.antiviral.2018.02.001
Accepted Manuscript: 10.1016/j.antiviral.2018.02.001
Mike Catton, Glenda Gray, Diane Griffin, Hideki Hasegawa, Stephen Kent, Jason
Mackenzie, Edward McSweegan, Natalia Mercer, Linfa Wang
PII: S0166-3542(18)30049-4
DOI: 10.1016/j.antiviral.2018.02.001
Reference: AVR 4240
Please cite this article as: Catton, M., Gray, G., Griffin, D., Hasegawa, H., Kent, S., Mackenzie, J.,
McSweegan, E., Mercer, N., Wang, L., 2017 international meeting of the Global Virus Network, Antiviral
Research (2018), doi: 10.1016/j.antiviral.2018.02.001.
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ACCEPTED MANUSCRIPT
Mike Cattona, Glenda Grayb, Diane Griffinc, Hideki Hasegawad, Stephen Kente, Jason
a
Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and
Immunity, Melbourne, Australia
b
South African Medical Research Council, Cape Town, South Africa
c
Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore,
MD, USA
d
National Institute of Infectious Diseases, Tokyo, Japan
e
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and
Immunity, Melbourne, Australia
f
Global Virus Network, Baltimore, MD, USA
g
Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore
Keywords:
* Corresponding author. Global Virus Network, 725 W. Lombard St., Rm. S-420,
Baltimore, MD 21201, USA.
E-mail address: [email protected] (E. McSweegan).
Abstract
The Global Virus Network (GVN) was established in 2011 to strengthen research and responses
to emerging viral causes of human disease and to prepare against new viral pandemics. There are
now 40 GVN Centers of Excellence and 6 Affiliate laboratories in 24 countries. The 2017
meeting was held from September 25-27 in Melbourne, Australia, and was hosted by the Peter
Doherty Institute for Infection and Immunity and the Institut Pasteur. This report highlights the
including the recent Zika epidemic, infections by human papillomavirus, influenza, HIV,
hepatitis C, HTLV-1, and chikungunya viruses, and new and emerging viruses in the Australasia
The Global Virus Network (GVN) was established in 2011 to strengthen research in
response to human viral diseases and to prepare for new viral pandemic threats (Mann, 2011).
The GVN now has 40 Centers of Excellence and 6 Affiliate laboratories in 24 countries (Figure
1). Network scientists meet annually to address research and collaborative priorities, learn about
each member's current work and plan future programs. These international conferences have
The 2017 international GVN meeting was held from September 25-27 in Melbourne,
Australia, in partnership with the Peter Doherty Institute for Infection and Immunity, and the
Institut Pasteur. It brought together directors of GVN Centers and their colleagues for three days
of scientific presentations and discussions of emerging and re-emerging viral threats. The
Melbourne meeting was the first GVN event open to non-GVN scientists and students.
Investigators, clinicians and students from area institutes and universities had the opportunity to
attend scientific sessions and present ongoing student work at a poster session to expand
opportunities for collaborative dialogue, particularly with young virologists. The main objectives
of the meeting were to present and discuss current findings in medical virology, including
advances in research on HIV vaccines; HTLV-1 infections among indigenous Australians; other
important Australasian viruses; and address the GVN's annual strategy for continued
development.
The formation of the GVN and the rationale for its structure have been previously
described (Akkina et al., 2017 ). Currently, the GVN consists of 40 Centers of Excellence and 6
threats. That mission is achieved through basic research, public education, and advocacy.
Diane Griffin, PhD, MD, University Distinguished Service Professor, and Alfred and Jill
Immunology at the Johns Hopkins Bloomberg School of Public Health—a GVN Center of
Excellence—was presented with the Robert C. Gallo Award for Scientific Excellence and
Leadership for her studies on measles and alphavirus encephalomyelitis, which have delineated
the role of host immune responses in virus clearance, vaccine-induced protection from infection,
tissue damage and immune suppression. Dr. Griffin also was cited for her leadership role within
the GVN’s international conferences and virology training programs, for making important basic
The award is named for Robert C. Gallo, MD, co-founder and director, The Homer &
of Maryland School of Medicine, and Co-Founder and Scientific Director of the GVN. Dr. Gallo
and his co-workers discovered interleukin-2 (IL-2), followed by the discovery of the first human
retroviruses, Human T-Cell Leukemia Virus-1 (HTLV-1) and HTLV-2. He and his colleagues
co-discovered HIV as the cause of AIDS and developed the first HIV blood test.
While not part of the formal GVN meeting, there was a morning session on HTLV-1
infection chaired by Damian Purcell of the Peter Doherty Institute and a closing summary by
Robert Gallo. Some of what was discussed has been published (Tagaya and Gallo, 2017; Gallo et
al., 2017), and it is anticipated that additional publications by other speakers will be forthcoming.
5. Scientific presentations
Antoine Gessain (Institut Pasteur, Paris) reviewed the epidemiology, origin and genetic
diversity of HTLV-1. In 2012, the EU Commission requested the European Centre for Disease
Prevention and Control (ECDC) to construct a map indicating all the HTLV-1 high-prevalence
areas in the world. By analyzing more than 1000 papers and hundreds of abstracts, Gessain and
colleagues provided the first complete epidemiological data (maps and tables) for the 203
world’s countries (ECDC, 2015). In most of the highly endemic areas, HTLV-1 is mainly
(mother-to-child and by sexual intercourse). More rarely, transmission may also occur by
transfusion or intravenous drug use. HTLV-1 originated from a simian retrovirus called simian
T-leukemia virus type 1 (STLV-1), which is widespread in Old World monkey and ape species.
The idea that HTLV-1 originated from STLV-1 is mainly based on the very high sequence
homology (African subtypes b, d, e, f) found between some STLV-1 strains and HTLV-1 found
transmission of STLV-1 to humans in natura and modes of acquisition remain quite scarce.
Gessain also reviewed reported cases of HTLV-3 and -4, and speculated on the future emergence
Lloyd Einsiedel (Baker Heart and Diabetes Institute, Australia) reported on HTLV-1
subtype C as a major cause of morbidity and mortality among indigenous Australians. The virus
is highly endemic to central Australia where more than half of all indigenous adults residing in
some remote communities are infected. Infection is associated with a rapidly progressive
various organ systems and an increased likelihood and severity of other infections, notably with
has been described; however, in this setting HTLV-1 infection is most often associated with
chronic respiratory disease, including life-threatening, severe bronchiectasis, and with invasive
bacterial infections (Einsiedel et al., 2012). The region has the highest reported prevalence of
adult bronchiectasis, and among the highest bloodstream infection incidence rates, worldwide.
The risk of bronchiectasis and the extent of pulmonary injury are strongly associated with the
HTLV-1 proviral load (pVL), which also predicts risk of invasive bacterial infection. The
association between HTLV-1 pVL and these life-threatening conditions is consistent with recent
findings that higher HTLV-1 pVL are associated with an increased risk of death in a large
prospective cohort of Indigenous adults (Einsiedel et al., 2016). High rates of HTLV-1 infection
and HTLV-1-associated diseases contribute substantially to the burden of ill health and early
Charles R. M. Bangham (Imperial College, U.K.) noted that HTLV-1 causes disabling
Staphylococcus aureus, with severe and sometimes fatal consequences. It has recently been
shown that HTLV-1 also causes and exacerbates bronchiectasis, bronchitis and bronchiolitis. The
risk of these HTLV-1-associated diseases is strongly correlated with the proviral load, which
frequently exceeds 10% of peripheral blood mononuclear cells (PBMCs). The virus, which is
non-cytolytic, drives proliferation of the infected CD4+ T cell, and the high proviral load is
Until recently, it was believed that HTLV-1 persisted in vivo chiefly by continuous oligoclonal
proliferation of about 100 clones of HTLV-1-infected CD4+ T cells. However, Bangham and
colleagues have shown that a typical individual carries between 10 4 and 105 clones, and the
proviral load – the chief correlate of disease – is determined by the number of clones, not by
oligoclonal proliferation. It was also believed that HTLV-1 was latent in vivo, but the existence
of the persistently activated CTL response in virtually all hosts strongly argues that the virus is
not latent but is frequently expressed. This suggests that the virus undergoes intermittent bursts
of expression in vivo.
(smFISH) that the provirus indeed undergoes intermittent, intense bursts of expression. Work is
under way to identify the factors that regulate the frequency, size and duration of these bursts. In
addition, spontaneous reactivation of HTLV-1 from latency in fresh PBMCs is governed by the
molecular oxygen availability and by glycolysis. Finally, he and colleagues discovered that
HTLV-1 alters host chromatin structure in the infected cell, by binding the chromatin
architectural protein CTCF, which regulates higher-order chromatin structure and gene
expression in vertebrates. This observation implies that HTLV-1 does a remarkable experiment
each infected host (Satou, et al., 2016). Studies are under way to test the hypotheses that CTCF
regulates HTLV-1 latency, and that the abnormal chromatin looping caused by CTCF can
discussed the clinical diagnosis and treatment of HTLV-1 diseases. The discovery of a cure for
cell leukaemia/lymphoma (ATLL) has been an ongoing process of refinement since the early
1980s. Martin presented summaries of more than 35 years of published and empirical
intervention options, including HTLV prevention strategies as part of the international HTLV
to HTLV-1 infection in Japan. Since the first report of ATL by Takatsuki’s group in 1977,
Japanese clinicians and researchers have made major contributions to understanding the virology
diseases such as HAM/TSP and HTLV-1 uveitis (HU). In the first decade of 2000, groups of
Japanese patients with HTLV-1-associated diseases petitioned the government for improved
health care and treatment, as well as continuous and strong support for clinical and basic
research. In 2010, the government organized a HTLV-1 Task Force composed of the Prime
Minister and government officials, representatives of patient groups, and medical specialists.
Subsequently, a nationwide campaign began in 2011 with screening for HTLV-1 antibody in all
pregnant women to prevent new mother-to-child transmissions. Counseling also was initiated for
HTLV-1 carriers and HAM/ATL patients. Some of the results of stepped-up government support
for HTLV-1 research and care have been reported (Satake et al., 2016; Nosaka et al., 2017).
three questions:
1. Are bats true reservoirs of emerging viruses? Since the discovery of rabies virus in bats
more than 100 years ago, bats have been known to carry zoonotic viruses. But the field
remained relatively “quiet” until the discovery of Hendra virus in Australian bats, which was
responsible for lethal outbreaks in horses and humans. Since then, bats have been confirmed or
suspected as reservoirs of several emerging viruses, including Nipah, SARS, MERS, Ebola and
Marburg viruses. Although scientists working in this field still debate whether bats are the true
reservoir of Ebola virus, for example, Wang pointed out that it took an international
collaborative team more than ten years to obtain convincing evidence of the bat origin of the
2. Are bats special in their ability to host viruses? There are two working hypotheses
associated with this question. First, it is difficult to induce experimental infections in bats with
many viruses lethal to humans and livestock. Second, bats can harbor more viruses on a per
species basis and there is a greater genetic diversity of viruses in bats than in other mammals.
Evidence has been gathered to support these hypotheses, although most of them are based on
retrospective studies of past literature. The most significant study examined a database of 2,805
mammal-virus associations and concluded that bats harbor a significantly higher proportion of
zoonotic viruses than any other mammalian order (Olival et al., 2017).
3. What makes bats special? Wang noted that bats have a long lifespan and are less prone to
cancer. He hypothesized that the evolutionary adaptation to flight has resulted in a unique
immune system significantly different from terrestrial mammals. He presented genomic data
indicating a more robust positive selection of genes responsible for DNA damage pathways
(Zhang et al., 2013). The most recently data obtained from his group suggests that the overall
dampening of inflammatory responses may be key to why bats can carry so many viruses, yet
Alex Greenwood (Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany)
introduced the concept of exogenous and endogenous retroviruses. While it is known that the
them completed their invasion millions of years ago obscuring the changes in virus and host
associated with them. The koala retrovirus (KoRV) is one of the few examples of a virus that is
(Tarlinton et al., 2006). By going through a collection of archived samples of modern wild and
zoo koalas dating back to 1891, Greenwood and his collaborators found crucial early events in
already resident in the host genome. These recombination events disable the exogenous
retrovirus making it less potentially harmful to the host while at the same time, the ancient
(Hobbs et al., 2017). In the context of trying to find the origin of KoRV, Greenwood, et al.
confirmed its close relationship to the gibbon ape leukemia virus (GALV). Both are likely from
Phylogenetically, two rodent viruses, Melomys bertoni retrovirus (MbRV) and Melomys
woolly monkey-like virus (MelWMV) are the closest to the KoRV/GALV-like viruses identified
to date (Alfano et al., 2016). Greenwood concluded that very close relatives of KoRV/GALV
have been circulating in a variety of mammalian taxa within the Australo-Papuan region east of
drug design. While most current antiviral strategies tend to target specific viral proteins and
inhibit their function, Brown described antiviral drugs that are modular in structure, consisting of
a viral attachment domain and an effector domain. In general, the attachment domain can be
antibody or any domain or motif structure that binds the surface of a virus. An effector domain
In collaboration with Aus Bio Ltd., the concept was tested against influenza virus. Entry of
endosome becomes more acidic, the viral hemagglutinin (HA) undergoes a conformational
change to reveal a hydrophobic fusion region that penetrates the endosomal membrane, thus
initiating the life cycle of virus replication inside the cell. Candidate drug molecules use an
attachment domain that binds to HA, and an effector domain that provides a negatively-charged
viral replication. Brown presented in vivo data on two drugs, MD185 and MD345, that provided
better protection in mouse and ferret models than did zanamivir. These constructs appear to
provide an extended therapeutic window until the adaptive immune system comes into play. The
long-duration activity of the drugs suggests they may be useful in prophylaxis, especially in a
pandemic context.
strain of human parechovirus type 3. Human parechovirus types 1-16 (HPeV1-16) are positive-
strand RNA viruses. Type 3 parechovirus (HPeV3) causes a severe disease in infants with
mortality up to 6% and potential long-term sequelae. As this was a newly recognised disease of
During the investigation of a 2015 HPeV3 outbreak, it was found that the genome of the
Australian viruses had undergone a major recombination event that took place between March
2012 and November 2013, followed by further virus evolution and possibly recombination. The
phylogenetic and network analyses from the Geelong group support a temporal evolution from
the first Australian recombinant virus sequence from November 2013 to March/April 2014 to the
2015 outbreak. Their data showed that the 2015 outbreak viruses are recombined from the
Yamagata 2011 lineage and an as yet unknown virus (Nelson et al., 2017).
This unknown virus, the donor of the non-structural coding region, may come from a not-yet
similar viruses do infect animals such as the recombinant HPeV4 detected in pigs in South
America (Nix et al., 2013). Finally, Alexandersen observed that the HPeV3 outbreaks seem to
follow a 2-3-year cycle, suggesting there may be another wave of HPeV3 outbreaks in Australia
in 2017/8.
Nobel Laureate Peter Doherty, (Peter Doherty Institute for Infection and Immunity,
immunity. The human family is constantly challenged by viruses, with epidemic/ pandemic
“immune escape” mutations in strains that are circulating in us. Vaccines that promote long-term
antibody-mediated immunity to “mop up” invaders can provide immediate protection though, of
course, as Doherty noted, we have no such products when something new and unexpected hits.
As our most intimate parasites, viruses grow only within living cells. As a consequence, part of
the process of recovery requires the elimination of these cellular “factories” of pathogen
production. The “hit man” of immunity that does this job is a circulating white blood cell, the
virus-specific, CD8+ “killer” T-cell, or cytotoxic T-lymphocyte (CTL) and the CTL is targeted
to cell surfaces via recognition of viral peptide bound to self MHC class I glycoproteins. Some
recent findings concerning HLA type and influenza prevention and susceptibility are of
particular interest, especially with regard to the greater susceptibility of indigenous populations
to influenza.
Maël Bessaud (Institut Pasteur, Paris), reviewed genetic recombination among positive-
strand RNA viruses and suggested enteroviruses as a convenient model for in vitro studies of
recombination. In particular, mostly non-homologous recombinant genomes were seen; that is,
genomes with deletions or duplications, which can subsequently evolve into homologous
recombinant genomes. Regions where recombination occurs more frequently have been
identified. These hotspots bound genomic domains that can be considered as modules used to
engender new mosaic genomes through recombination. These results illustrate how
recombination is able to generate a wide genetic and phenotypic diversity and can promote the
camels as models for Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) infection.
Experimental intranasal inoculations with MERS-CoV produces only upper respiratory tract
infection (URT) and mild clinical signs. Infectious virus is only detected in the trachea, large
bronchi and tracheobronchial lymph nodes, while viral RNA is more widely detectable in the
nose, the upper and lower respiratory tracts and in extrapulmonary lymphoid and visceral tissue.
Nasal, tracheal and bronchial inflammation are present, without gross lesions. A similar clinical-
pathological picture is seen after intranasal MERS-CoV inoculation of domestic new world
camelids, producing either no clinical signs (alpacas) or mild mucus secretion (llamas), with
MERS-CoV detectable in the URT (nasal swabs and trachea) of both species, and cleared from
the URT 7-10 days post-infection, concomitant with antibody responses. Pigs also may be
experimentally infected and show the presence of viral RNA in nasal swabs, trachea and bronchi
until 7-10 days postinoculation. Only very limited transmission to direct contact mates is seen
under experimental conditions. Experiments performed to date suggest that other large animal
domestic species such as horse, sheep and goat are not susceptible to MERS-CoV infection.
Ramesh Akkina (Colorado State University, USA) described new and improved
humanized mouse (hu-mouse) models that harbor a transplanted human immune system to study
viral pathogenesis, evolution, latency, and human immune responses to HIV, dengue and Zika
viruses (Schmitt et al., 2017). He outlined the use of Hu-mice as an alternative to in vitro viral
outgrowth assays (qVOA), which are currently the gold standard for measuring latent HIV in
cure research, but often fail to detect very low levels of replication-competent virus as evidenced
by the “Boston patients (Hayden, 2013).” Akkina showed that Hu-mice also provide a potential
animal model to study HIV-2, and for testing a three-drug formulation of anti-retrovirals (Hu et
al., 2017). Hu-mice are susceptible to HIV-2 infection and show persistent viremia and CD4 T-
Akkina also described how ideal animal models of human cell infections and human
immune responses are lacking for the flaviviruses, dengue and Zika. In dengue pathogenesis
studies, hu-mice were shown to be permissive for productive infection resulting in viremia
developing human neutralizing anti-dengue IgM and IgG antibodies. Recent experiments showed
that hu-mice (BLT mice) are also susceptible to Zika virus with chronic viremia lasting more
than 220 days. Virus-infected human monocytes/macrophages, B cells and hematopoietic stem
cells were found in bone marrow (Schmitt et al., 2018) Human neutralizing antibodies are
detected highlighting the use of this model for future vaccine testing.
Peter Revill (The Doherty Institute in Melbourne) described the International Coalition
to Eliminate Hepatitis B Virus (ICE-HBV), which was established in 2016 to accelerate research
collaborative partnerships working towards a cure for chronic hepatitis B (CHB). Over 250
million people worldwide are chronically infected with HBV, and even though a prophylactic
vaccine and effective antiviral therapies are available, no post-infection cure exists. This is of
concern in the Asia-Pacific region, where over 118 million people, including 239,000
Recent advances in the field, such as the identification of the NTCP receptor for viral entry and
improved cell culture and animal models, are facilitating a new era in cure research worldwide
(Watashi et. al., 2014; Revill et. al., 2016). Through its global network, ICE-HBV is working to
poorest countries often are not vaccinated against HBV, including much of Africa, where 75
million people are chronically infected. With immigration of peoples from highly endemic
Furthermore, African HBV genotypes and the natural history of African CHB remain poorly
characterized, particularly in children. African CHB is associated with unique genotypes such as
E and A1, although the prevalence of these genotypes outside Australia is poorly described.
Bannister and colleagues found that the HBV genotypes in African children and adults
living in Melbourne largely reflected their country of origin, including genotypes associated with
viruses. Early e-antigen seroconversion was observed, and HBV variants that have previously
been associated with more severe clinical disease progression were seen in around 40% of
children before adulthood. In vitro studies of these genotypes showed differences in the way the
African clones replicated and produced viral proteins, which may have implications for how
these strains produce disease or can be treated. These findings have important ramifications for
patient monitoring and treatment guidelines, particularly in the pediatric setting, in Australia.
hepatitis C virus (HCV) infections affect approximately 71 million people worldwide and is a
major cause of morbidity, liver cancer, liver transplantation and mortality. Currently, the goal of
HCV therapy is to achieve a “functional cure,” which is defined as a sustained virologic response
(SVR) in which no detectable plasma HCV RNA is detected 12 weeks after therapy. Recently,
oral direct-acting antiviral (DAA) therapy has been shown to be safe, tolerable and highly
effective in achieving SVR without the use of interferon-alpha, which has been associated with
adverse events, long duration, and modest SVR. This is a major milestone in the management of
chronic hepatitis C. Still, most people infected with HCV are not aware of their status, only
twenty percent are in care and less than ten percent are treated. Greater awareness among both
providers and patients is required to optimize the care continuum. Approaches that enable
testing strategies for marginalized patients are critical to achieving elimination of hepatitis C
HIV and HCV are important global viral pathogens, for which the landscape of
Glenda Gray (South African Medical Research Council) provided an update on current
HIV vaccine efficacy trials. Although anti-retroviral treatment (ART) is highly successful, it is
expensive, can lead to drug resistance and is difficult to fully implement. Further, half of all HIV
infections are transmitted by subjects within the first 5 months of their infection, often before
they are aware of their infection. It is widely recognized that a HIV vaccine will be an essential
tool in control of the HIV epidemic, especially in regions with high prevalence, such as Southern
Africa. Over the last 20 years, HIV vaccine strategies have evolved from simple protein
approaches or single vectors designed to induce cytotoxic T cells towards heterologous prime-
boost regimens designed to induce broader immunity. The Thai RV 144 trial of a canarypox
vector-gp120 protein prime boost vaccine regiment showed 31.2% efficacy (Rerks-Ngarm et al.,
2009). The 5400 subject HVTN 702 trial is now under way, to see if it can improve upon this
efficacy. At the time of the GVN meeting, 1600 subjects had already been enrolled. A two-stage
Gray also reported that planning for a second prime-boost efficacy trial in southern
Africa, the 2600-subject HVTN 705 trial using an adenovirus type 26 vector-gp140 boost
regimen was well advanced. This regimen has showed significant efficacy in monkey trials
(Barouch et al., 2015) and it has been announced subsequent to the GVN meeting that the trial is
efficacy-study). Separate from the prime-boost vaccine efficacy trials, another efficacy trial of a
passively transferred monoclonal neutralizing antibody (VRC01) is under way in both South
Africa and North America (HVTN 703 and 704 studies). The VRC01 antibody is effective in
preventing infection in monkey models and can reduce HIV levels in infected humans (Gray et
approaches to an HIV cure. HIV remains latent despite ART, meaning that treatment must
continue for life. Latent HIV can be reactivated with certain drugs that activate virus
transcription, such as histone deacetylase inhibitors, with the hope that the reactivated virus will
then be cleared (the so-called “shock and kill” strategy (Deeks, 2012)). However, recent clinical
trials of these drugs show that their effect is modest and that effects on gene transcription can be
non-specific and prolonged (Sogaard et al., 2015). Newer, more specific, more effective and less
Purcell’s group has developed assays to measure transcription of HIV mediated more
specifically by HIV-1 Tat that lend themselves to high-throughput screens for inhibitors. He
described a novel class of drugs, the amidothiazoles, that appear to specifically activate Tat-
mediated HIV transcription in T-cell lines, with minimal toxicity. Their precise target mode of
action is being studied, as is their ability to reactivate HIV from blood samples from infected
people. This is a promising approach that should ultimately expand the armamentarium of
Margaret Hellard (Burnet Institute, Melbourne) presented the efforts of her group and
collaborators to eliminate HCV transmission through multipronged efforts to cure large numbers
of patients. The efficacy and simplicity of newer DAAs for hepatitis C provides a window to
reduce transmission by reducing the numbers of viremic subjects. Modelling shows this should
HCV can be treated. The cost of the newer drugs is coming down in many parts of the world and
Australia’s approach of universal access is facilitating larger scale treatment uptake. Increased
rapid testing for HCV, assessment of liver fibrosis, and treatments administered to transmission
networks in communities are likely to be required to achieve these goals (Pedrana et al., 2017).
5.6 Arboviruses
Arboviruses are some of the most widely distributed viral pathogens that also cause
frequent episodes of epidemic disease. Many factors contribute to the emergence and spread of
these viruses, including globalization, changes in vector competence, climate change, and
spillover events affecting the vectors and the ensuing victims (Gould, et al., 2017). This session
difficulties with controlling dengue virus (DENV) infections globally, and highlighted strategies
that are currently being employed against mosquitoes to limit the replication and transmission of
many arbovirus infections, including DENV. He detailed current approaches employed by the
World Mosquito Program (WMP; previously known as Eliminate Dengue) to establish the
intriguingly ability to limit virus replication in co-infected cells (Moreira et al., 2009).
and the WMP has initiated similar programs in DENV-endemic areas such as Indonesia, Brazil,
Columbia, Vietnam and India. Simmons underlined some of the challenges of the WMP,
including communication with the local population, the cost of large-scale implementation,
measuring milestones and evidence-based outcomes, and developing methods to measure the
impact of Wolbachia on disease incidence. Still, current results and projections look encouraging
Scott Weaver (University of Texas Medical Branch, Galveston, USA), Chair of the
GVN task force on Zika virus (ZIKV), provided a timely update on the dramatic emergence of
ZIKV in South and Central America in 2016, and a historical view on the spread of ZIKV from
Africa to Asia to the South Pacific and now to the Americas (Aliota et al., 2017). Weaver
microcephaly) and the significant impact infection has on the unborn fetus in infected pregnant
women. One of the most interesting recent observations is the precipitous decline in reported
Zika cases in 2017. The reasons for this are currently unclear though increasing “herd immunity”
may be a factor.
Weaver highlighted recent advances in ZIKV research, emphasising the large volume of
research dedicated over the past few years, and culminating in numerous vaccine candidates
under clinical trials and the development of nonhuman primate models to investigate
pathogenesis. One of the most important considerations from these studies is the potential of
DENV/ZIKV disease in subsequent infection. He identified many of the research gaps that still
remain, particularly in diagnosis, as many of the current diagnostic tests are cross-reactive but
developments with a specific ZIKV anti-NS1 kit look encouraging. (GVN is supporting a ZIKV
serum bank to aid in the development of better diagnostics). Additionally, the proposed herd
immunity generated against ZIKV in the Caribbean and Latin America may hinder the
populations, and 2) market vaccines in the absence of significant new cases (Ferguson et al.,
2016). The principles that underlie the unique pathogenesis and transmission routes of ZIKV still
remain unanswered.
Robert Garry (Tulane Medical School, USA) discussed the development of antibodies
against Lassa fever virus (LASV) and Ebola virus (EBOV), and provided an overview of the
history of these two viruses and efforts to coordinate and establish collaborative networks to
provide outreach and education to affected African communities (Yozwiak et al., 2016). He
described the generation of human monoclonal antibody cocktails targeting the LASV
glycoprotein and the technologies available to produce large quantities of highly specific human
monoclonals, which have proven effective in nonhuman primate models (Mire et al., 2017).
These developments and the construction of bivalent and trivalent vaccine candidates expressing
stabilized LASV and EBOV glycoproteins are encouraging tools against lethal haemorrhagic
fever viruses.
Marc Lecuit (Biology of Infection Unit, Institut Pasteur and Inserm, France) described
the role of the cellular unfolded protein response (UPR) in the development of ZIKV disease. He
presented evidence that the UPR contributes to neurogenesis and that upregulation of the UPR in
neuronal progenitor cells can impact development, resulting in microcephaly in a mouse model.
He showed compelling data indicating that ZIKV induces the UPR in neuronal progenitor cells;
this was reflected in dysregulated neuronal development and reduced brain mass in ZIKV-
infected fetal mice (Gladwyn-Ng, et al., 2017). Therapeutic interventions alleviating the UPR
John Fazakerley (The Peter Doherty Institute for Infection & Immunity, Australia)
and cellular tools for the study of Chikungunya virus; further the understanding of the virus-
vector relationship; develop new diagnostics, antivirals and a vaccine; and advance
understanding of the pathogenesis of the disease and its sequelae. He also presented two studies
of experimental animal models for investigating whether an alphavirus (Semliki Forest virus)
that causes encephalitis can persist in the brain and whether an alphavirus (Chikungunya virus)
reported on the innate immune response mediated by type I interferon (IFN), and the resulting
carried out at a single-species level, often lacking the comparative power necessary to understand
key evolutionary features of this pathway. Palmarini and colleagues determined common and
unique properties of the interferomes for multiple vertebrate species and developed an open
access webserver to mine the dataset. They reported finding a “core” of 62 ISGs, including genes
not previously associated with IFN, underscoring the ancestral functions associated with the type
IFN response. They showed that gene expansion contributed to the evolution of the IFN system
and that interferomes are shaped by lineage-specific pressures. Furthermore, an analysis of genes
Joshua Hayward (Burnet Institute, Australia) noted that viral infections of bats typically
produce no signs of clinical disease, raising questions about what innate immune differences
might exist between bats and other mammals. The APOBEC3 gene family encodes antiviral
DNA cytosine deaminases, which are restriction factors with important roles in the suppression
of diverse viruses and genomic parasites. Hayward and colleagues characterized the megabat
(family Pteropodidae) APOBEC3 genes and show that pteropid bats possess the largest and most
diverse array of APOBEC3 genes identified in any mammal reported to date. Several bat
ABOEC3 proteins have been shown to be capable of restricting retroviral infectivity, using HIV-
role for APOBEC3-mediated restriction of ancient bat retroviruses, and a molecular clock
analysis indicates that the expansion of APOBEC3 genes coincided with the extinction of
pteropid LINE-1 retroelements (Hayward, et al., 2013). These findings reveal the first group of
antiviral restriction factors identified in bats with extensive diversification and divergence
vectors in Asia. More than 430, 220 and 240 different mosquito species have been identified in
Thailand, Vietnam, and Cambodia, respectively. Little is known about ticks, however, and even
less about sandflies and biting midges. Compared to the diversity of vectors, very few
arboviruses have been identified beyond the “big four”: dengue virus (serotypes 1-4); Japanese
encephalitis virus; chikungunya virus; and more recently, Zika virus. Strategies for vector control
in most Asian countries are few—with rare successes and numerous failures. There appear to be
several reasons for the vector control stalemate, including a paucity of field research, as well as
Fontenille posed a number of questions about the region and the emergence of new
viruses, asking: How can we effectively control vectors? How can we assess the risk of
emergence and outbreak within the frame of environmental, social and climate change? What do
we know about the biology and evolution of mosquitoes (for example, Ae. aegypti vs Ae.
albopictus), and mosquito-virus co-adaptation in Asia? Should Southeast Asia expect the
emergence of Zika virus? Fontenille reviewed these issues and made recommendations for a
more active, holistic research approach involving virologists, zoologists, ecologists, social
Anthony L. Cunningham (University of Sydney, Australia) described the “find me” and
“eat me” signals that attract human dermal dendritic cells (dDCs) to Langerhans cells (LCs)
infected with herpes simplex virus (HSV), and facilitate recognition and uptake of apoptotic LCs
(Botting, et al., 2017). He and his colleagues assessed the expression of chemokines by HSV-
infected LCs and corresponding chemokine receptors on dDC subsets, as well as apoptotic
receptors that may recognize and facilitate their interactions. These studies help to define the
mechanisms of uptake and viral antigen transfer between LCs and dDCs, leading to subsequent
differential presentation to CD4+ and CD8+T-cells, which may define potential dendritic cell
Zhiwei Chen (AIDS Institute and Department of Microbiology, Hong Kong SAR,
nutrients. Inflammatory mediators such as infiltration and activation of CD8+ T-cells, pro-
inflammatory cytokines and CD4 T-cell depletion likely contribute to these changes in the
intestine following local immune activation. Chen and colleagues have discovered that a subset
of gamma-delta T-cells (∆42PD1+Vδ2) also may contribute to innate immune activation and
mucosal damage during acute HIV infection (Cheung, et al., 2017). These cells may serve as
targets for the investigation of diseases with mucosal inflammation, in addition to initial HIV
mechanisms of HIV-1 persistence and developing innovative strategies for treatment and a
been studied as latency-reversing agents, and clinical studies have shown that single and multiple
administration results in induced viral RNA transcription and protein in CD4+ T-cells from
ART-suppressed HIV+ subjects (Wu, et al., 2017). Furthermore, applying novel screening
strategies for latency reversal agents in the presence of a sensitizing agent, such as a HDACi, can
be a useful approach in identifying new mechanisms and alternative therapies for latency
intervention. Notably, the exploration of cure strategies targeting the latent HIV reservoir also
highlights a need for new assays and research tools to quantify viral burden in tissue and various
body fluids. The rare incidence of latently-infected cells, for which robust phenotypic markers
are still needed presents a challenge to identifying these cells and measuring changes in viral
Sarah Palmer (Centre for Virus Research, University of Sydney, Australia) reported that
full-length HIV sequencing techniques revealed the majority of persistent HIV provirus in cells
is genetically defective during antiretroviral therapy (Hiener et al., 2017). However, the
distribution of intact proviruses within memory CD4 + T-cell subsets from participants who
initiated therapy during either acute or chronic infection showed the proportion of intact provirus
was significantly different across cell subsets. Cells expressing the HLA-DR activation marker
and effector memory cells contained the highest proportion of intact HIV genomes. In addition,
clonal expansions of intact proviruses were identified indicating that proliferating cells
contribute to the latent reservoir. The HLA-DR marker identifies cells containing a high
frequency of intact HIV genomes; therefore, assays quantifying the persistent HIV reservoir
should include these cells. Determining the type of cells and cellular mechanisms contributing to
persistent replication-competent HIV is crucial for future efforts aimed at HIV eradication.
5.9 Finale
Ricky Mentha (Baker Heart and Diabetes Research Institute, Australia) reported that
Aboriginal populations residing in remote locations have limited general knowledge of infectious
diseases, modes of transmission, and preventative public health measures. Exposure to an array
of communicable diseases is prevalent, and morbidity and mortality are significant. Effective
partnerships with local Aboriginal stakeholders are critical to improving knowledge of infectious
diseases and developing preventative strategies derived from a well-thought-out research agenda.
Mentha described many pressing needs, including: research grounded in the principles of social
justice and equity; community consultations and partnerships; building capacity with Aboriginal
researchers and community members; and translating findings into policy, practice and health
research in remote Aboriginal populations, but it can be done in ethical and culturally sensitive
ways that contribute to reducing exposure to poverty-related infectious disease that impact on
Kanta Subbarao (WHO Collaborating Centre for Reference and Research on Influenza,
Australia) presented recent data on replication and viral properties governing the airborne
transmission of influenza virus 2009 pandemic A/H1N1 in a ferret transmission model, and
described some of the complex viral and host interactions that influence the transmissibility
Frederick Kristensen (CEPI, Oslo, Norway) described the recently established Coalition
for Epidemic Preparedness Innovations (CEPI). The organization was launched in January, 2017
with an initial investment of more than $500 million provided by the governments of Norway,
Japan and Germany, the Bill & Melinda Gates Foundation and the Wellcome Trust. In addition,
the European Commission agreed to co-fund some CEPI projects with €200 million. Other
funds will be available from Australia, Belgium and Canada. At its launch, CEPI issued a call for
proposals to develop vaccines against three viral agents: MERS-coronavirus, Lassa and Nipah
On October 1, 2017, Christian Bréchot, MD, PhD became the new GVN President
Bréchot held other leadership positions with the French National Institute of Health and Medical
Research (Inserm), the Institut Mérieux, and the BIOASTER Technology Research Institute. He
hepatology and cell biology. In 1982, Dr. Bréchot received a Doctor of Medicine from Paris
Descartes University (Paris VII) and a PhD in biochemistry from the Paris Descartes
University. Throughout his career, his research has focused on HBV and HCV, particularly
regarding their role in liver cancer and to the molecular mechanisms that drive liver regeneration
and cancer. He is a member of numerous scientific committees and societies and has received a
myriad of prestigious awards. Dr. Bréchot has authored more than 350 articles in medical and
scientific journals.
While there are new changes to the GVN headquarters staff, several other activities have
continued, including the collection of acute and convalescent sera from confirmed Zika patients
to aid in developing new diagnostics. The serum bank is funded by a grant from the Allergan
Foundation, and samples are stored at the University of Texas Medical Branch in Galveston,
Texas. In addition, Shyamasundran Kottilil and colleagues at the Institute of Human Virology in
Baltimore have continued a project with the GVN to expand a training model for health care
providers using DAA treatment for hepatitis C patients in India (Mathur et al., 2017). The
training program is funded by the Gilead Foundation. Similarly, a pilot study to develop an
Pradesh, India also is under way, and is funded by the John C. Martin Foundation.
GVN's HTLV-1 task force members published a commentary recommending the current
name for HTLV-1 be changed back to its original name (human T-cell leukemia virus-1), in
keeping with its oncogenicity and pathogenesis (Gallo, et al., 2017). Other GVN investigators
published work on the oncogenicity of HTLV-1 (Tagaya and Gallo, 2017). Members of the GVN
task force on Zika virus also published a major review on what has been learned about Zika in
the first two years of the epidemic in the Americas, and what gaps remain (Aliota MT et al.,
2017).
During 2017, the Network expanded the number of cooperating research centers by
adding the Mérieux Foundation in Lyon, France, and the Rega Institute for Medical Research at
the University of Leuven in Belgium (Figure 1). These two new centers are expected to
GVN staff will continue to solicit patient serum samples for the Zika serum bank in
collected Zika virus isolates is continuing in cooperation with the World Reference Center for
Emerging Viruses and Arboviruses (WRCEVA), which is funded by the National Institute of
The GVN will host the fifth annual Short Course on Medical Virology for young
investigators in the summer of 2018. The Short Course attracts an international class of 15-20
postdoctoral students and fellows for five days of meetings and lectures with experts in medical
virology research and clinical practice. Information about the course and registration is available
online at http://gvn.org.
The 2018 international GVN meeting will be in Annecy, France during November 28-30.
It will be co-hosted by the Research Center for Emerging Infections and Zoonoses at the
includes: Christian Bréchot, GVN President, USA; Huber Endtz, Scientific Director at the
Fondation Mérieux, France; Robert Gallo, Co-Founder & Scientific Director, GVN; William
Hall, Co-Founder, GVN, University College Dublin, Ireland; Ab Osterhaus, Director of the
Research Center for Emerging Infections and Zoonosis (RIZ), Germany; and Marc Lecuit,
We thank the participants who presented their data at the 2017 International GVN Meeting. We
thank The Peter Doherty Institute for Infection and Immunity, and the Australasian Society for
HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) for their outstanding management of
the meeting and related events. Support also was provided by numerous sponsors, including,
Abbvie, the Australian Centre for HIV and Hepatitis Virology Research (ACH 2), the Australian
Centre for Hepatitis Virology, Bioniz, Club Melbourne, CSL Limited, FORT National
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IPT
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Figure 1. GVN Centers of Excellence and associated laboratories. Each center has a director
who has made significant contributions to the literature; high productivity in terms of
publications; has served as a regional resource for research, diagnostics and treatment;
programs that interact with other centers in the region, and outreach programs with less
developed countries. Current Center Directors are listed at: http://gvn.org/gvn-centers.
Highlights
6 Affiliates in 24 countries.
The 2017 Global Virus Network (GVN) Meeting was held in Melbourne, Australia from
September 25-27.
New data were presented on various aspects of medical virology, therapies, and emerging
International collaboration is critical to developing new and effective viral vaccines and
therapeutics.
The 2018 international GVN meeting will be held on November 28-30 in Annecy,
France.