Keppler Lab - Research
Development of Multi-transgenic Rat and Rabbit Models of HIV-1 Infection
A major bottleneck for the development of novel therapeutic strategies against HIV is the lack of a highly permissive and readily available small animal model, as normal mice, rats and rabbits cannot be infected with HIV since they impose multiple cellular barriers to HIV replication. Recent scientific advances have demonstrated that specifically engineered transgenic rodents can overcome individual species-specific barriers to HIV replication.
Schematic representation of consecutive steps (1-6) in the HIV replication cycle.
Barriers to HIV-1 replication at distinct steps in primary mouse, rat, and rabbit cells, are indicated by X. The major barrier at virus entry is common to all non-human species and can be overcome by transgenic expression of the HIV receptor complex.
Via transgenesis, knock-out approaches and virus adaptation we propose to develop multi-transgenic rat and rabbit models that is highly susceptible to infection by HIV-1 and that recapitulates key aspects of the disease in humans, thus enabling the development of improved pharmacotherapy and possibly vaccines to fight HIV.
Towards this goal, we have pioneered the generation of rats transgenically expressing human CD4 and human CCR5 (together referred to as the HIV receptor complex) and human Cyclin T1 in relevant target cells. Transgenic Sprague-Dawley rats display a high proviral load in lymphatic organs early after intravenous HIV-1 challenge, while viremia in plasma is low and transient.
These animals allow a rapid and predictive preclinical testing of antiviral compounds targeting virus entry, reverse transcription, and integration and have contributed to the in vivo-evaluation of a novel, semen-derived pathogenicity factor as well as vaccine candidates.
Our goals in projects involving these multi-transgenic small animals are:
- Characterize and overcome remaining barriers to efficient HIV-1 replication
- Conduct studies on viral transmission and pathogenesis
- Validate and mechanistically dissect novel antiviral strategies, including pharmacotherapy, vaccines and gene therapy approaches, prior to advancement to phase I clinical trials
More recently, Dr. Hanna-Mari Baldauf, nee Tervo, has identified rabbits as a species with even fewer intrinsic barriers to HIV replication. Based on this work, she is currently advancing the development of genetically modified rabbits to serve as a more permissive model for lentiviral infection in her newly established research group (Research Group Baldauf).
Furthermore, we are currently establishing a cutting-edge humanized mouse model employing gene edited hematopoietic precursors as a platform to study the biology of HIV infection ex vivo and in vivo.