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Frank Kirchhoff advances AIDS research by posing the right questions

Frank Kirchhoff, an AIDS researcher from Ulm, has learnt to pose important questions and find the right answers during his post-graduate studies. This recipe has brought him and his research group international recognition and makes him one of the best AIDS researchers worldwide. Important publications within a very short time and numerous awards are clear evidence of his outstanding achievements. In addition, he has just started a clinical trial for an HIV inhibitor. Kirchhoff is even more optimistic about a peptide that he discovered in human semen.

Prof. Dr. Frank Kirchhoff. (Photo: University Hospital Ulm)
At first glance, Kirchhoff’s success in posing the right questions does not seem to be a particularly great talent. Huge hopes had been raised by a new AIDS vaccine, but in vain. Twenty-five years after the discovery of HIV-1, AIDS researchers met in the Parisian Pasteur Institute in May 2008 and admitted that they needed to go back to the drawing board (Nature, Vol. 9, August 2008, p. 823 ff.). At the end of July, the American Institute of Infectious Diseases, which covers about 80 per cent of the worldwide HIV vaccine research expenditure, asked the AIDS researchers to return to their laboratories. This appeal indirectly confirms Kirchhoff’s research activities, showing that basic questions have yet to be resolved.

In the Primate Centre in Göttingen where Kirchhoff studied and did his doctorate, some researchers also deal with AIDS. The 47-year-old virologist initially wanted to study botany and ecology, but ended up in microbiology and virology. His diploma thesis dealt with the genomic analysis and biological properties of HIV-2, a virus that was discovered in 1986.

Postdoc at the Harvard Medical School

In a research group led by Ronald Desrosiers, the young scientist learnt that it is necessary to pose important questions and also get answers. With this, Kirchhoff alludes to the field of molecular biology which he feels is occasionally aloof, losing sight of the patients. At the beginning of the 1990s, Desrosiers and his team believed they had discovered a recipe for an AIDS vaccine. Their idea did not convince Kirchhoff, who was finally able to substantiate his ideas in his habilitation - that an AIDS vaccine was somehow feasible, but its clinical application difficult and full of risks.

Kirchhoff later accepted a post at the University of Erlangen and in 2001, he was offered a professorship at the Institute of Virology at the University of Ulm. He decided to stay in Germany and enjoy the freedom of research it offered, instead of going to an American organisation (National Cancer Institute), where he regarded research as being well equipped but sometimes too rigid for his liking.

Why do humans become sick and not apes?

Back then, Kirchhoff did not have plans to focus on vaccine development, a complex and expensive venture, stating “we are far from being able to develop a vaccine.” He was sure that the money available in Germany was insufficient (back then about 0.5%, today no more than 5% of the funds available for this type of research in the States) to focus on such a venture effectively.

Instead, the virologist started to focus on viral pathogenesis and was looking for answers to the question: Why does HIV-1 make people sick, but similar ape viruses are harmless for their hosts? Kirchhoff has already come up with some answers. For example, he found that similar viruses (SIV) are found in more than 40 ape species that do not normally develop AIDS. Kirchhoff assumes that there are two reasons for that: firstly, the apes became infected with these pathogens a long time ago and have adapted to them. Secondly, the human AIDS virus has lost a function that would normally block the activation of infected T-helper cells.

Does the lack of a specific receptor cause problems for the body’s defence?

The majority of SIV (or to be more exact, the viral nef protein) remove a receptor (CD3) from the surface of T-helper cells. This receptor is important for an immune response to occur and hence the body’s defence mechanisms become ineffective. This function only got lost in the virus strain that crossed from chimpanzees to humans. Only recently, researchers were able to show (PlosPathogene, 10.1371/journal.ppat.1000107) that this function protects the virus’s natural host from the loss of CD4-positive T-helper cells. This supports the hypothesis of why HIV is so aggressive in humans.

HIV infection leads to the apoptosis of many infected T-cells; in addition, the release of cytokines leads to the programmed suicide of neighbouring cells. Kirchhoff has plans to work together with researchers at the Primate Centre in Göttingen. The research involves African vervet monkeys. He plans to test what he has already achieved in cell culture, namely blocking this function in SIV (as in HIV). He hopes that this will then result in the virus becoming pathogenic in its natural host.

Treasure hunt in body fluids

NMR structure of the VIRIP-FP complex shown as surface plot (left) of rod model (right). White: HIV 1 gp41 fusion peptide; coloured: VIRIP derivative 165. (Photo: Kirchhoff)
NMR structure of the VIRIP-FP complex shown as surface plot (left) of rod model (right). White: HIV-1 gp41 fusion peptide; coloured: VIRIP derivative 165. (Photo: Kirchhoff)
While he was working at the University of Erlangen, Kirchhoff met the researcher Wolf-Georg Forssmann from Hanover who is a specialist in producing peptide/protein libraries from natural body fluids or tissues using new methods. It had been known for a long time that there were compounds in the body that were able to control viruses. Kirchhoff and his colleague Jan Münch from Ulm screened about a million proteins, messenger substances and fragments of larger compounds and found an inhibitor. This inhibitor had a length of 20 amino acids and blocked HIV by binding to the gp41 fusion peptide of the virus, thereby preventing the virus from intruding into the cell membrane.
Optimised VIRIP variants. P4-CCR5 cells were infected in the presence of VIRIP (black square) or VIRIP derivates (blue) and T20 (red). The infection was determined three days after infection using a luminescence test. (Figure: Kirchhoff)
Optimised VIRIP variants. P4-CCR5 cells were infected in the presence of VIRIP (black square) or VIRIP derivatives (blue) and T20 (red). The infection was determined three days after infection using a luminescence test. (Figure: Kirchhoff)
The systematic analysis of approximately 600 derivatives enabled the researchers to increase the activity of the original peptide 200-fold. In the meantime, one of the synthetic variants (Virip) has entered a phase I/II study in Hanover. The study is financed through industry and private investors. A growing number of HIV strains are turning resistant to current drugs, which has already become a severe problem in some industrialised countries. Against this background, Kirchhoff and his team proved that HIV-1 cannot easily develop resistance to their synthetic VIRIP variant in cell culture.

Looking for the most plausible

It seems that more people are dying from AIDS now compared to 20 years ago when the first AIDS drug was discovered. Kirchhoff therefore concludes that the drugs are of little help for the majority of AIDS sufferers. At the same time, Kirchhoff is very optimistic about one of his recent discoveries.

While searching for inhibitory substances in human sperm, Kirchhoff discovered aggregating peptides (Sevi, short for semen enhancer of viral infection) which form small fibrils and promote HIV’s ability to infect human cells 100,000-fold. Sevi might also play an important part in the sexual transmission of the virus, which only results in AIDS in nine out of ten cases. Now the researchers have to find out whether the peptides also lead to the promotion of viral infection in vivo and how it can be blocked effectively.
HIV-loaded SEVI fibrils bind to cells. Cells are dyed blue, SEVI fibrils green and HIV-1 particles red. Nearly all virus particles are associated with SEVI. (Photo: kindly provided by Walther Mothes, Joseph Luna and Pradeep Uchil; Yale, New Haven, USA)
HIV-loaded SEVI fibrils bind to cells. Cells are dyed blue, SEVI fibrils green and HIV-1 particles red. Nearly all virus particles are associated with SEVI. (Photo: kindly provided by Walther Mothes, Joseph Luna and Pradeep Uchil; Yale, New Haven, USA)
Even if the in vivo effect is not as strong as the effect seen in vitro, the researchers’ discovery could offer a new target for preventing the spread of AIDS more effectively than existing vaccines and microbicides. Kirchhoff’s discovery would then explain why many anti-AIDs substances are ineffective in the presence of sperm, and why the vaginal microbicides women use to protect themselves against infection fail. Kirchhoff further explains that many millions of euros have been invested into microbicide trials although it was not at all certain whether the microbicides would have any effect against the virus, given the nature of the fluid in which the virus was carried.

Causalities instead of correlations

Kirchhoff has some very exciting research plans. In the field of pathogenesis, Kirchhoff is hoping to uncover causalities rather than just correlations. In terms of primates this means asking the following questions: Does the loss of the virus’s ability to remove the CD3 receptor from the cell surface and hence prevent the activation of T-cells, really lead to immunodeficiency, even in natural primate hosts?

Kirchhoff and his team will continue looking for additional inhibitors in human body fluids, including human haemofiltrate, breast milk and saliva. He is working closely with Prof. Heinz Maier from the German Federal Army Hospital in Ulm with the goal of this research being to investigate the transmission ways and fluids of different viruses.

Kirchhoff also plans to find out whether the peptide fibrils also play a role in other sexually transmitted diseases, for example hepatitis C or herpes simplex viruses. Then the researchers will have to find effective strategies for blocking Sevi.

The key questions remain the same

Kirchhoff will once again be able to rely on the art of asking important questions. After approximately 25 years of AIDS research, it is still unknown why HIV causes AIDS, whether the HI viruses destroy the cells directly or whether this happens through the death of non-infected cells. Instead of looking into these important questions, Kirchhoff finds that too much time is used to look into the molecular mechanisms. For him the key question remains: can infected people be treated or the spread of the virus prevented?

Kirchhoff’s research group does not have to worry about third party funds. Recently, and frustrated by inappropriate EU research funding, Kirchhoff decided to apply for NIH (National Institute of Health) funding and was successful. This was a particularly important success considering the fact that about eight per cent of American researchers succeed with their NIH applications. It will probably not take long before Kirchhoff’s group publishes another outstanding paper as they have an excellent reputation in the field. Kirchhoff was also invited to hold a plenary lecture at the 15th Conference on Retroviruses and Opportunistic Infections 2008 in Boston, MA.

Literature:
Schindler, Michael; Münch, Jan, et al.: Nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1, in: Cell 125, 1055-1067, June 16, 2006

Münch, Jan; Ständker, Ludger et al: Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide, in: Cell 129, 263-275, April 20, 2007.

Münch, Jan; Rücker, Elke et al.: Semen-Derived Amyloid Fibrils
Drastically Enhance HIV Infection, in: Cell 131, 1059-1071, December 14, 2007.

Schindler M., Schmökel J., Specht A., Li H, München J. et al. (2008): Inefficient Nef-Mediated Downmodulation of CD3 and MHC-I-Correlates with Loss of CD4+T Cells in natural SIV Infection. PLoS Pathog 4(7): e100107. doi : 10.1371/journal.ppat.1000107.

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