Biology Reference
In-Depth Information
Introduction
The ability of human cytomegalovirus (HCMV), like all herpes viruses, to establish
a lifelong persistent infection plays a crucial role in the long-term carriage of this
opportunistic pathogen in the human host. It is likely that HCMV persistence, in
vivo, involves sites in the host which continually produce low levels of virus.
However, it is now clear that it also involves sites which carry the viral genome
latently in the absence of any productive infection.
Although HCMV causes few overt symptoms following primary infection of
healthy individuals, significant morbidity and mortality is observed in the immu-
nonaïve, immunocompromised and immunosuppressed (Ho 1990; Zaia 1990).
Primary infection is an important factor in HCMV-mediated disease (see the
chapter by W. Britt, this volume), particularly following congenital infection
(Griffiths and Walter 2005). However, reactivation from latency is a major cause of
disease in certain transplant patients (both solid organ and bone marrow transplan-
tation) and also in late-stage HIV patients suffering from AIDS (Adler 1983; Rubin
1990; Sissons and Carmichael 2002). Consequently, developing an understanding
of the mechanisms that regulate latency and reactivation in vivo is of paramount
importance for future clinical intervention.
In order to do this, a number of fundamental questions about the basic biology
of HCMV need to be addressed: Firstly, in which cells does the latent virus reside?
Secondly, in which cells does the virus reactivate. Thirdly, what regulates this
latency and reactivation?
The ability to detect latent HCMV, particularly prior to the development of highly
sensitive techniques such as the polymerase chain reaction (PCR), is in contrast to
the ease of detecting productive HCMV infection during disease. Acute HCMV
infection is manifest in numerous tissues (Rubin 1990; Sissons and Carmichael
2002). Epithelial, endothelial, smooth muscle, stromal, fibroblast and neuronal cells
all support lytic HCMV replication in vivo (Sinzger et al. 1995; Plachter et al. 1996;
see the chapter by C. Sinzger et al., this volume) and, consequently, HCMV pathology
can be seen in a diverse range of organs throughout the body. In contrast, HCMV
latency appears to be restricted to subpopulations of cell types.
Latency, Carriage and Reactivation of HCMV
in the Cells of the Myeloid Lineage
Some of the first instructive observations regarding HCMV latency came from clinical
studies. Although it was extremely difficult to detect infectious virus in the blood of
normal healthy individuals, it was evident that blood transfusions from healthy sero-
positive donors often resulted in the transmission of HCMV to blood donor recipients
(Adler 1983). However, the incidence of this transmission was significantly reduced
if leukocyte-depleted blood products were used (Yeager et al. 1981; Tolpin et al.
