HIV Infection and Opioid Treatment Enable the Engraftment of Kaposi Sarcoma-like Tumors into Immunocompetent Mice

Abstract

The Kaposi Sarcoma herpesvirus (KSHV) causes Kaposi sarcoma (KS), primary effusion lymphoma, a lymphoproliferative disease (KSHV-multicentric Castlemans disease), and a cytokine inflammatory syndrome (KICS). These diseases occur more frequently, though not exclusively, among people living with HIV or other types of immune dysregulation. While limited KS can regress with immune reconstitution, such as through antiretroviral therapy (ART) in people living with HIV, there are currently no curative treatments for advanced KS. Preventive or therapeutic vaccines targeting KSHV could have a significant clinical impact; however, the development and testing of such strategies have been limited by the lack of preclinical models that faithfully recapitulate KS, including the presence of infected spindle cells and a relevant immune microenvironment. HIV/AIDS is an important cofactor for KS, and globally, the majority of individuals with KS are HIV-infected. Current evidence indicates that HIV-1 may enable KS progression through immunosuppression and promote pathogenesis by inducing inflammatory cytokines and producing secreted regulatory proteins like Tat and Nef. The design and testing of new therapeutic approaches based on pathogenesis are hampered by the lack of models that replicate KSHV oncogenesis in the context of HIV/AIDS. In the present study, we demonstrate that KSHV-infected cells can form tumors in an immunocompetent mouse model, but only when these mice are pretreated with EcoHIV and morphine, both of which have immunomodulatory and pro-inflammatory effects. These tumors exhibit gene expression profiles and immune microenvironments that closely resemble those observed in human KS lesions. This novel KSHV tumor model in immunocompetent mice provides a valuable platform to test immunotherapeutic strategies for KS, including immunomodulatory agents, targeted antibody therapies, checkpoint inhibitors, and vaccines. Author SummaryKaposi sarcoma (KS) is a cancer caused by the Kaposis sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). A vaccine against this virus could prevent or cure this malignancy. However, there are no good animal models with an immune system to test new immunization approaches. The possibility of having KSHV-driven tumors develop in immunocompetent mice due to EcoHIV infection presents a unique opportunity to create an AIDS-KS mouse model suitable for testing immune-based therapies and KSHV vaccines in a scenario that replicates important aspects of AIDS-KS. These first-in-kind murine models incorporating a biologically relevant mouse HIV infection tool make our models unique and original, with the potential to provide novel mechanistic and pathobiological insights.