KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice.
To develop an animal model of Kaposi sarcoma-associated herpesvirus (KSHV) infection uniquely suited to evaluate longitudinal patterns of viral gene expression, cell tropism, and immune responses, we injected NOD/SCID mice intravenously with purified virus and measured latent and lytic viral transcripts in distal organs over the subsequent 4 months. We observed sequential escalation of first latent and then lytic KSHV gene expression coupled with electron micrographic evidence of virion production within the murine spleen. Using novel technology that integrates flow cytometry with immunofluorescence microscopy, we found that the virus establishes infection in murine B cells, macrophages, NK cells, and, to a lesser extent, dendritic cells. To investigate the potential for human KSHV-specific immune responses within this immunocompromised host, we implanted NOD/SCID mice with functional human hematopoietic tissue grafts (NOD/SCID-hu mice) and observed that a subset of animals produced human KSHV-specific antibodies. Furthermore, treatment of these chimeric mice with ganciclovir at the time of inoculation led to prolonged but reversible suppression of KSHV DNA and RNA levels, suggesting that KSHV can establish latent infection in vivo despite ongoing suppression of lytic replication.
Parsons
Christopher H
CH
Myles H. Thaler Center for AIDS and Human Retrovirus Research, Department of Microbiology, University of Virginia Health Systems, Charlottesville, Virginia 22908, USA.
Adang
Laura A
LA
Overdevest
Jon
J
O'Connor
Christine M
CM
Taylor
J Robert
JR
Camerini
David
D
Kedes
Dean H
DH
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology; D019070:Cell Lineage; D015774:Ganciclovir / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000276:immunology; D012514:Sarcoma, Kaposi / Q000276:immunology / Q000821:virology; D013154:Spleen / Q000166:cytology / Q000821:virology; D019737:Transplants; D014771:Virion / Q000378:metabolism / Q000648:ultrastructure
D015703:Antigens, CD; D000956:Antigens, Viral; D000998:Antiviral Agents; D009687:Nuclear Proteins; C109540:latency-associated nuclear antigen; D015774:Ganciclovir