Background: Kaposi sarcoma (KS) is an important complication associated with HIV infection. Currently there are no animal models to study KS or its etiological agent, human herpes virus-8 (Kaposi’s sarcoma associated herpes virus, KSHV). Since human B cells are targets of KSHV infection we hypothesized that humanized mice repopulated with human lymphocytes would be susceptible to infection with KSHV. 

Methods: We recently described the development of a novel humanized mouse model in which virtually all aspects of human hematopoiesis as well as innate and adaptive immune responses are faithfully recapitulated. Since these humanized mice were derived from the reconstituted Bone marrow of mice previously implanted with fetal Liver and Thymic tissues we adopted the designation NOD/SCID-hu BLT mice (or BLT mice). These animals received an intrasplenic inoculation of KSHV. Viral loads in peripheral blood and multiple organs were monitored by real-time PCR. To confirm the latent state of viral infection we reactivated the viral lytic promoters using valproic acid (VPA), an effective inhibitor of histone deacetylase (HDAC), to induce lytic replication and detectable viremia in peripheral blood.  We injected KSHV latent infected BLT mice i.p. with VPA (200 mg/kg/day) and analyzed the blood for the presence of virus following the treatment.

Results: Following infection with KSHV, the virus established a latent infection with spontaneous reactivation detected in peripheral blood by real time PCR (4 and 10 weeks post inoculation). Injecting VPA into the KSHV latently infected BLT mice resulted in plasma viremia in all animals treated. None of the latently infected control animals (injected with PBS) produced spontaneous viremia during the same time frame. KSHV was predominantly identified in the spleen followed by lung, liver and kidney in individual animals. VPA treatment resulted not only in increased viral load in peripheral blood but also in a significant increase in the copy number of KSHV in the spleen (p<0.002, Student’s t-Test) of the injected animals suggesting active viral replication in response to VPA.

Conclusion: This is the first demonstration of in vivo KSHV infection in a humanized mouse model where virus replication can be induced.  Since BLT mice are also susceptible to HIV infection we anticipate the possibility of establishing a co-infection model that could recapitulate important aspects of KS in the context of HIV infection.