Biology Reference
In-Depth Information
Subsequent studies from this institution and other groups have also documented
the importance of T lymphocyte responses and late disease in hematopoietic cell
transplant recipients and in solid organ recipients (Lacey et al. 2002; Boeckh et al.
2003; Bunde et al. 2005). A recent study argued that generation of CMV-specific
CD8
+
lymphocytes responses in hepatic allograft recipients failed to correlate with
protection from late infection with CMV (La Rosa et al. 2007). Furthermore, it has
been reported that development of detectable HCMV-specific CD4
+
lymphocyte
responses in the early posttransplantation period (1
st
month) lessened the risk for
acute rejection, HCMV disease, and long-term loss of lumen cross-sectional area,
suggesting that early control of virus replication was an important risk factor for
late disease associated with HCMV infection (Tu et al. 2006). In contrast to this
report, a very recent study suggested that increased CD4
+
lymphocyte responses to
HCMV are associated with chemokine-mediated endothelial damage, a process that
is thought to be essential in the development of vascular disease in the transplanted
allograft (Bolovan-Fritts et al. 2007).
The results of these studies have raised important questions about the nature of
protective immunity against HCMV, the role of antiviral responses in inflammation
associated with allograft damage, and the role of antiviral prophylaxis in increasing
the risk for late disease associated with CMV infections. In addition, these studies
have suggested that the presence of CD8
+
responses may not be a surrogate of
protection from late disease, a finding first observed by Riddell and colleagues
nearly 15 years ago (Walter et al. 1995; La Rosa et al. 2007). Understanding what
constitutes durable protective immunity in this population with exaggerated risks
for invasive CMV infection secondary to immunosuppression could help elucidate
the parameters of protective immunity in normal hosts, a prerequisite for design and
testing vaccines to limit disease from congenital infections.
In agreement with what has been observed in the mouse, the predominant CTL
response following HCMV infection was initially proposed to be directed against a
limited set of virus-encoded antigens. The three dominant targets of HCMV-
specific CD8
+
CTL were pp65 (UL83), pp150 (UL32) and IE72 (UL123) based on
studies reported from a number of different laboratories (McLaughlin-Taylor et al.
1994; Boppana and Britt 1996; Gillespie et al. 2000). A more definitive study
defined the virus-specific CD8
+
and CD4
+
responses to all possible open reading
frames of HCMV in a group of seropositive individuals (Sylwester et al. 2005). The
results of this study provided evidence that the immune system has directed its
dominant responses at the most abundant virus-encoded proteins, which in many
cases are virion structural proteins (Sylwester et al. 2005). The breadth and magnitude
of the T lymphocyte response to CMV was surprisingly large. In fact, in the normal
immunocompetent host over 10% of circulating T lymphocytes are human CMV-
specific (Sylwester et al. 2005). This finding suggested that in these donors, either
the virus-specific response was completely ineffectual in the control of virus replica-
tion or conversely, it represented a host response that was required to overcome the
vast number of immune modulating functions of the virus. Interestingly, two of the
HCMV CTL targets are antigens encoded by early-late genes, and, thus, would
