INSIGHTS | PERSPECTIVES
lead to lifelong carriage (10) (see the figure).
Unlike NrHV, LCMV is a natural pathogen
of mice, so this recapitulation of LCMV-like
data with the new NrHV model is reassuring that similar immunologic responses are
involved. The key difference is that LCMV
establishes a widespread infection, whereas
NrHV, like HCV, replicates in the liver. Because presentation of antigen to T cells in
the liver can lead to immune tolerance, there
may be much to learn about T cell activation
that is of wide immunologic relevance (11).
The study of Billerbeck et al. leaves several
questions unanswered—which may now be
answerable—about the specific mechanisms
involved in hepatocyte clearance of NrHV by
T cells, the critical functions of early CD4+ T
cell help, and local mechanisms of regulation
of CD8+ T cells in the liver.
Billerbeck et al. suggest that the mouse
model of NrHV infection may prove valua-
ble in developing and testing HCV vaccines.
Recent World Health Organization model-
ing data (from the 2017 WHO Global Hepa-
titis report) indicate that there are around
1.75 million new HCV infections annually
worldwide and that, currently, the number
of patients newly infected is higher than
the number dying from, or being cured of,
infection. Furthermore, because HCV is of-
ten a “silent” infection, patients are only
diagnosed once advanced liver disease is
established. Because prevention is clearly
better than a cure, an effective HCV vac-
cine is likely to play an essential part in
global HCV eradication and control. So far,
there is one vaccine in a phase 2 clinical
trial that is testing protection of at-risk
groups (12). The regimen is based on vac-
cination with a recombinant simian ade-
novirus that expresses HCV nonstructural
proteins (NS3, NS4A, NS4B, NS5A, and
NS5B), boosted by a recombinant poxvirus
expressing the same proteins (13). How-
ever, although this regimen induces strong
and durable CD4+ T cell and CD8+ T cell re-
sponses, there are still no good correlates
of protection. Furthermore, there is a large
amount of antigenic diversity among HCV
strains, making predictions about vaccine
efficacy in geographically distinct popu-
lations difficult. Thus, further testing of
similar vaccine approaches in this animal
model of NrHV infection could be very val-
uable. Additionally, vaccines that induce
broadly neutralizing antibody responses
have been in preclinical and clinical trials
(14), and this approach could also be read-
ily tested in the new model.
LCMV has been an important instructor
of immunology, especially regarding viral persistence. However, NrHV may have
something particular to teach us about viral hepatitis—features needed for successful
control of infection and for elucidating the
mechanisms that underlie persistent viral infection. Given that hepatitis B and C
viruses affect around half a billion people
worldwide and are a leading (and rising)
cause of death globally (15), lessons from
NrHV are worth learning. j
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A pathway protects cells
from mutations caused
by sugar-derived aldehydes
By Felix A. Dingler and Ketan J. Patel
In a now famous paper for gastro- nomes, French physician and chemist Louis C. Maillard described in 1912 the spontaneous reaction between sugars and proteins at high temperatures (1). Sugars, often thought of as chemically
inert, possess a carbonyl group (in the
form of aldehydes and ketones) that, at
elevated temperatures, is highly reactive
toward free amine groups in proteins, ultimately forming advanced glycation end
(AGE) products. The so-called “Maillard”
reaction is the reason why the browning
of meat reveals delicious flavors; AGE
carbonyl adducts alter the aromatic and
gustatory properties of biomolecules present in cooked food products. But should
we care about the natural decomposition
of sugars or the production of aldehydes
and ketones in our bodies? As suspected
by Maillard himself, the answer is an emphatic yes because carbonyls are ubiquitous and can compromise cell health. On
page 208 of this issue, Richarme et al. (2)
identify that an unusual protease “cleans
up” dicarbonyl adducts on nucleotides as
a protective mechanism. Interestingly, this
enzyme, called DJ-1, also repairs proteins
that have been similarly damaged by carbonyl modification. The study points to a
possible new mechanism for repairing endogenous DNA damage.
The body produces enough monocarbonyls (such as formaldehyde) to severely compromise life if we did not possess protective
mechanisms. In the case of aldehydes, our
cells have a two-tier protection mechanism.
Tier 1 consists of metabolic detoxification
of monocarbonyls; tier 2 consists of a specific DNA repair pathway that ensures that
damage caused by molecules escaping detoxification are promptly repaired (3, 4).
Medical Research Council Laboratory of Molecular Biology,
Francis Crick Avenue, Cambridge Biomedical Campus,
Cambridge CB2 0QH, UK. Email: firstname.lastname@example.org
Clearance versus persistence
In human HCV infection, early activity of CD4+ T cells
and CD8+ T cells is linked to early immune control
over weeks or months in some patients (top graph).
In LCMV (clone 13) infection, a similar time course
is seen but early CD4+ T cell depletion (red arrow)
leads to failure of control (middle panel). In the new
rat-derived NrHV model, early CD4+ T cell responses
play a similar pivotal role (bottom graph). The graphs
are modeled from published data (4, 7, 10).
Human HCV infection
3 to 6 months
3 to 6 months
3 to 6 weeks
CD4+ T cell
Mouse NrHV infection
Mouse LCMV infection
CD4+ T cell