Transmission and Acquisition of Human Herpesvirus 8

Lawrence Corey, MD; Jeff Vieira, PhD; Meei-Li Huang, PhD

Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpes 8, is the causative agent of Kaposi's sarcoma, and is also found in two HIV associated proliferative diseases, primary effusion lymphoma, and multicentric Castleman's disease. KSHV is a gamma-2 herpesvirus (rhadinovirus), and like all herpesviruses it establishes a lifelong infection of the host with both lytic and latent modes of replication. KSHV contains a number of genes with potential for roles in cellular proliferation, immunomodulation, signal transduction and transformation, including virus specific ORF K1, K3, K5, and viral homologs of cellular genes such as v-cyc, v-Bcl, v-MIP-I, II, III, v-GCPR, v-IRFs. Unlike herpesviruses like HSV or HCMV, KSHV readily establishes a latent infection in in vitro cell culture, facilitating the study of the biology of the latent state to cellular proliferation and immune evasion, as well as identifying factors that activate the virus to lytic replication.

Previous work has demonstrated the presence of infectious KSHV in saliva, the construction of recombinant KSHV, the generation of a variety of cell types containing latent KSHV, and the finding that HCMV can activate lytic replication of KSHV.
Currently, the following areas of KSHV research are being pursued.
1. Recombinant virus. A recombinant KHSV has been developed which allows the determination of latent and lytic gene expression in living cells by the expression of fluorescent proteins. This virus is being used to examine factors activating KSHV lytic replication, such as cellular differentiation, cytokines, and HIV. Because this virus allows the easy determination of cells with lytic replication it is also being used to study immunomodulating lytic genes. Recombinant viruses with disruptions of various KSHV genes are also being developed for the study of gene function in virus infected cells.
2. Analysis of latent gene expression and function. Primary, as well as other cell types, have been established that exhibit only latent viral replication. These cells are being used to determine gene expression, and the function of latent proteins such as ORF73 and v-IRFs in KSHV infected cells.
3. Relationship between neutralizing antibodies to KSHV and KS. An assay has been developed that facilitates the determination of neutralizing antibodies to KSHV. This is being used to study cohorts of subjects with and without KS to analyze the role of the humoral response in KS development.

Publications

Vieira, J. Huang, M-L. Koelle, D. M., and Corey, L. Transmissible Kaposi's sarcoma-associated herpesvirus (humanherpesvirus 8) in saliva of men with a history of Kaposi'ssarcoma. J. Virol. 1997 71:7083-7.

Vieira, J., O'Hearn, P., Kimball, L., Chandran, B., and Corey, L. Activation of Kaposi's sarcoma-associated herpesvirus (HHV8) lytic replication by human cytomegalovirus. J. Virol. 2001, 75(3): 1378-86.