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Indirect Effects of Cytomegalovirus Infection
Prophylaxis and Pre-emptive Therapy for Figure 2: Inhibitory Effects of Cytomegalovirus
Cytomegalovirus and Their Influence on
Infection on Immature Dendritic Cells
16
Indirect Cytomegalovirus Effects
Although increasing data are available regarding different
A Mock
TB40/E
therapeutic strategies and their efficacy in CMV disease, there are
still many questions left concerning these therapeutic regimens
and their impact on indirect CMV effects.
As confirmed by Khoury et al., pre-emptive therapy allows low-level
asymptomatic CMV replication to occur.
29
A disputable benefit of
pre-emptive antiviral chemotherapy can be anticipated in terms
of the indirect effects of CMV infection.
30,31
Prophylactic treatment
regimens suppress viral replication and may be more efficient in
preventing both CMV disease and life-threatening indirect CMV
effects, such as acute graft rejection or higher incidence of
opportunistic infections. When treated with ganciclovir or
valganciclovir, this has been at the expense of an increase in late-
onset HCMV disease
32,33
due to a delayed recovery of the cellular
immune response. Some antiviral drugs induce neutropenia and
further inhibitory effects on T cells, which may increase the risk of
secondary infections.
12,34
Evidence to date does not allow us to determine whether
prophylactic therapy would be superior to pre-emptive therapy with
regard to indirect CMV effects. Further studies are needed to clarify
this question since pre-emptive therapy is mainly applied in
B
Number Virus MHC Class 1 CD80 CD86 CD40
Due to the limited number of agents 1 Mock
TB40/E ↓↓↑ND
with anti-cytomegalovirus efficacy,
2 Mock
both prophylactic and pre-emptive
TB40/E ↓↓↑ND
3 Mock
therapies are applied and no clear
TB40/E ↓↓↑↓
advantage can yet be demonstrated
4 Mock
TB40/E ↑↓ ↓ ↑↓ ↓
for one of the therapies.
5 Mock
TB40/E ↓↓↑↓
6 Mock
patients at an intermediate risk of CMV disease (CMV-seropositive
TB40/E ↓↓↑↓
transplants) bearing an elevated risk of complications such as graft
barb2down = downregulation in infected dendritic cells (DCs); barb2up = upregulation in infected DCs,
rejection or opportunistic infections. There are few data available
barb2downbarb2up = no alteration; ND = not determined; mock = uninfected DC; TB40/E = DC infected by
human cytomegalovirus (CMV) strain TB40/E.
supporting the hypothesis that prophylactic therapy decreases the
A: Major histocompatibility complex (MHC) class I molecules are downregulated post
risk of graft rejection. A 50% reduction in the rate of graft rejection
infection (p.i.) with the CMV strain TB40/E double immunofluorescence in situ analysis of
MHC molecules (yellow) and viral antigens (green). B: Comparison of immunomodulatory
was observed in patients who received CMV prophylaxis.
18
Two
surface molecules in CMV-infected versus mock-infected immature DCs by fluorescence-
meta-analyses
7,35
came to the conclusion that CMV prophylaxis has
activated cell sorting (FACS).
no significant influence on acute rejection or graft loss in SOT
patients. One of these studies
7
demonstrated a significant reduction complications such as an increased risk of graft rejection or
of bacterial and protozoan infections when the patients received dysfunction and a high incidence of opportunistic infections. In
CMV prophylaxis. Currently available data may lead to the principle, CMV prophylaxis, by suppressing low-level viraemia,
suggestion that prophylactic therapy may be beneficial for should be able to prevent both the direct and indirect effects of
preventing the indirect effects of CMV infection. However, with CMV infection and might be the antiviral strategy of choice
available antiviral agents there is no evidence that prophylactic regarding indirect CMV effects.
therapy is superior to pre-emptive treatment regarding overall
survival and morbidity. Prolonged administration of the current antiviral agents (e.g.
ganciclovir) inhibits CMV specific immune recovery and facilitates
Summary the occurrence of late-onset CMV disease after discontinuation of
The indirect effects of CMV infection in the immunocompromised CMV prophylaxis. Not only is CMV infection one of the most
host remain an important topic for future research projects. These important and life-threatening complications in the immuno-
effects are associated with low-level viraemia that might interact compromised host, it is also a target well-suited for cellular
with the host immune response and cause serious life-threatening immunity.
36
Immunotherapeutic approaches provide an attractive
EUROPEAN HAEMATOLOGY 43
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