Research of Frank Kirchhoff

One of the main interests of Frank Kirchhoff’s research is to determine the factors that contribute to the high virulence and world-wide spread of pandemic HIV-1 strains. Four different groups of HIV-1 (M, N, O and P) have been described until today. Each group is the result of an independent zoonotic transmission of a simian immuno-deficiency virus (SIV) from chimpanzees or gorillas to humans. Interestingly, only HIV-1 group M strains have spread worldwide, whereas the other three groups have remained largely restricted to West Africa. Kirchhoff and his colleagues found that differential adaptation to the human host may explain why only one of these viral transmissions is responsible for the AIDS pandemic. Specifically, their results show that only pandemic HIV-1 M strains evolved a fully functional viral protein U (Vpu) that counteracts tetherin (a cellular factor that blocks virus release) and degrades CD4 (the primary receptor of HIV) to promote the release of fully infectious viral particles. In contrast, Vpus from non-pandemic HIV-1 group O and P strains remained unable to antagonize human tetherin. Furthermore, most Vpu proteins of the rare group N viruses gained only modest anti-tetherin activity and lost the CD4 degradation function. The exception is the Vpu of the most recently discovered HIV-1 N strain, which counteracts tetherin as effectively as group M Vpus. Thus, non-pandemic HIV-1 strains are still adapting to humans and their transmission fitness may increase in the future. Kirchhoff and his team also want to clarify why monkeys that are naturally infected with SIV usually do not develop AIDS. It is known that high levels of chronic immune activation and programmed cell death drive progression to AIDS in humans and that HIV-1 increases the activation of T cells. Kirchhoff’s group found that most SIVs exhibit a quite different phenotype and use their Nef protein to efficiently suppress the activation and programmed death of central memory T cells. Thus, fundamental differences in Nef function help to explain why damaging hyper-activation of the immune system is observed in progressing HIV-1 infection but absent in asymptomatic naturally SIV-infected monkeys. Understanding the basis for the efficient spread of pandemic HIV-1 group M strains and the lack of disease progression in natural SIV infection may help to develop new preventive and therapeutic approaches.

Kirchhoff’s second major research focus is the isolation, characterization, and optimization of natural factors that modulate viral infections. In cooperative studies with Prof. Wolf-Georg Forssmann (Hanover), Kirchhoff and his colleagues have screened complex peptide-protein libraries from natural sources, such as blood, semen, spleen, saliva and breast milk for natural compounds affecting HIV infection. These studies have led to the discovery of several HIV inhibitors. One of them, VIRIP, blocks HIV-1 entry by a novel mechanism, i.e. direct binding to the gp41 fusion peptide. A cooperative phase I/II clinical trial showed that mono-therapy with an optimized VIRIP derivative suppressed viral replication without causing severe side effects. Kirchhoff’s research also used this approach to identify endogenous factors involved in the sexual transmission of HIV. Unexpectedly, his team found that semen contains peptides that form amyloid fibrils that capture HIV virions and boost viral infection. These amyloid aggregates may play an important role in the sexual transmission of HIV and represent new targets for its prevention.

Based on this discovery, Kirchhoff and his colleague Jan Münch have developed fibril-forming peptides suitable to improve and facilitate retroviral gene transfer in basic research and clinical applications. Notably, their recent data suggests that amyloid aggregates in semen may also play a role in male fertility. In their ongoing studies they have identified novel inhibitors and enhancers of HIV in breast milk and an as yet unknown, natural CXCR4 antagonist that not only blocks infection by CXCR4-tropic HIV-1 strains but also promotes the mobilization of stem cells and suppresses the migration of cancer cells. Thus, the screening of natural peptide-protein libraries allows to discover and optimize agents with highly unexpected activities that have implications beyond HIV/AIDS.

CV of Frank Kirchhoff

Frank Kirchhoff studied biology at the University of Göttingen. From 1988 to 1991, he performed his Ph.D. thesis describing a novel HIV-2 strain at the German Primate Center. Subsequently, from 1991 to 1994, he was a post-doc at the New England Primate Research Center of Harvard Medical School in Southborough, MA (USA), with a main focus on live-attenuated AIDS vaccines and the function of the accessory Nef protein of primate lentiviruses. In 1994 he established his own research group at the Institute of Virology of the University of Erlangen-Nuremberg under the directorship of Prof. Dr. Bernhard Fleckenstein. In 2001 he was awarded a full professorship in virology at the University of Ulm and became director of the newly funded Institute of Molecular Virology in Ulm in 2009. Kirchhoff has received numerous honors for his work, including the Gottfried Wilhelm Leibniz Prize of the German Research Foundation (DFG) in 2009. He is a member of, among others, the National Academy of Sciences Leopoldina and the National AIDS Advisory Council.

Prof. Dr. Reinhard Kurth, chairman of the Foundation Council of the Schering Stiftung, congratules Frank Kirchhoff on the award and explains the Schering Stiftung’s choice as follows: “Frank Kirchhoff is one of the outstanding scientists in the field of molecular virology. With his research, he has made an important contribution to understanding the transmission of the HI virus and opened up new possibilities for therapy and prevention.”