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Keppler Lab - Research

HIV reservoir and immunodestruction

HIV/AIDS has become one of the most devastating pandemics in recorded history. AIDS is the fourth-biggest global killer and the leading cause of death in Africa. HIV/AIDS persists as a major cause of morbidity also in Western societies, since currently available pharmacotherapies can only partly control, but not cure this immunodestructive viral infection. Our laboratory seeks to better understand the pathological interplay of HIV with the host’s immune system and its target cells with the goal of providing new approaches for prophylaxis and therapy.

Resting CD4 T cells are at the center of several hallmarks of HIV pathogenesis: (i) Their depletion in the course of untreated HIV infection leads to the ultimate development of severe immunodeficiency, (ii) they are not permissive for productive HIV infection due to highly effective intrinsic immune responses, (iii) yet constitute a key cell type of the latent HIV reservoir, from which the virus rebounds upon discontinuation of antiretroviral therapy. We are seeking molecular understanding of this complex and in part seemingly contradicting virus-host interaction.

To this end, we have developed innovative methodology for the rapid, efficient and activation-neutral gene editing of polyclonal resting CD4 T cells allowing unprecedented functional analyses (Albanese, Ruhle et al., Nature Methods 2021).

We are addressing the following questions in resting CD4 T cells:

  • Establish the relevance of cellular restriction factors as part of the intrinsic immune response in regulating HIV infection and the development of viral latency
  • Decipher how accessory viral proteins influence the course of HIV infection
  • Identify cellular pathways involved in HIV-induced cell death ex vivo and in vivo

In collaboration with Prof. Roberto Speck’s laboratory in Zürich, Switzerland, we are establishing a cutting-edge humanized mouse model employing gene edited hematopoietic precursors as a platform to study the biology of HIV infection in vivo.