The 40-year quest for a vaccine against human cytomegalovirus (HCMV) infection has been partially met by targeting the major envelope glycoprotein B (gB). However, the complex natural history of HCMV and the virus ability to infect a wide range of host cell types illustrate the central role cellular tropism plays in HCMV pathogenesis and emphasize the need for a vaccine that targets additional viral determinants of cellular tropism. Multiple genes located within the UL/b' region (UL128-UL154) of the HCMV genome have been implicated in regulating virus entry into epithelial and endothelial cells and modulating several host immune responses mounted against HCMV infection. We utilized virological, histopathological, and epidemiological tools to characterize the relationship between rhesus cytomegalovirus (RhCMV) cellular tropism and the pattern of viral infection in vivo and illustrated the potential of targeting products of genes within the UL/b' region in future vaccine developments. To address this, we inoculated rhesus macaques with three RhCMV strains that vary in their UL/b' coding content. RhCMV UCD52 and UCD59 encode a full complement of open reading frames (ORF) in the UL/b' region; RhCMV 68-1 lacks the UL128 complex essential for endothelial/epithelial tropism, and alpha-chemokine-like ORFs; and RhCMV 180.92 tropic for endothelial/epithelial cells but lacks viral determinants of host immune evasion.
Two histopathological hallmarks were observed with the acute infection with RhCMV UCD52 and UCD59 strains: neutrophilic inflammation and infected endothelial cells, both of which were observed during recurrent RhCMV disease in animals coinfected with wild-type RhCMV and simian immunodeficiency virus (SIV). In contrast, animals inoculated with RhCMV 68-1 were noted for an absence of neutrophilic infiltrates and infected endothelial cells, demonstrating the role of UL128 complex in epithelial/endothelial tropism in vivo and further suggest that the long-term pattern of viral infection is determined in large part by the earliest virus-host interactions. Further investigations using RhCMV 180.92 demonstrated lower levels of plasma viremia, limited systemic dissemination, low levels of tissue virus titers, and absent or low level of viral shedding in urine and saliva, compared to the in vivo pattern of a minor RhCMV 180.92 variant present in the virus stock potentially carrying the full complement of UL/b' region. These results demonstrate the possibility that other ORFs, independent of UL128 complex, within the UL/b' region may determine in vivo viral replication, dissemination, and shedding of RhCMV.
Finally, RhCMV neuromuscular disease was identified in 10.5% of all SIV-infected animals and 6% demonstrated direct RhCMV infection of skeletal muscles. HCMV has been implicated by association in the pathogenesis of HIV-associated myopathies. However, in vivo studies failed to demonstrate a direct evidence of HCMV infection of skeletal muscle cells. Our results indicate that RhCMV is linked to skeletal myositis and suggest that human HCMV may be a causative agent for similar pathologies in HIV-infected humans.
|Advisor:||Barry, Peter A.|
|Commitee:||Abel, Kristina, Luciw, Paul A.|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 74/03(E), Dissertation Abstracts International|
|Subjects:||Pathology, Virology, Veterinary services|
|Keywords:||Betaherpesvirus, Cell tropism, Cytomegalovris vaccine, Rhabdomyositis, Rhesus cytomegalovirus, Rhesus cytomegalovirus infection|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be