# Biographical Feature: In memoriam Pierre Tiollais
(1934–2024)

Christian Bréchot, Patrick Charnay, Hugues de Thé, Anne Dejean, Marie-Louise Michel, Pascal Pineau, Pierre Sonigo, Simon Wain-Hobson, Yu Wei, Jean Weissenbach

► To cite this version:

Christian Bréchot, Patrick Charnay, Hugues de Thé, Anne Dejean, Marie-Louise Michel, et al. Biographical Feature: In memoriam Pierre Tiollais (1934–2024). Journal of Virology, 2025, 99 (2), pp.e02125-24. 10.1128/jvi.02125-24. hal-04997228

HAL Id: hal-04997228

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# Biographical Feature: In memoriam Pierre Tiollais (1934–2024)

Christian Bréchot,¹ Patrick Charnay,² Hugues de Thé,³ Anne Dejean,⁴,⁵ Marie-Louise Michel,⁵ Pascal Pineau,⁴,⁵ Pierre Sonigo,⁶ Simon Wain-Hobson,⁵ Yu Wei,⁵ Jean Weissenbach⁷

**AUTHOR AFFILIATIONS** See affiliation list on p. 3.

**KEYWORDS** hepatitis B virus, vaccine

<figure><img src="image_3.png" /></figure>

Pierre Tiollais, a French physician-biologist who cloned and sequenced the genome of hepatitis B virus (HBV) and developed a recombinant hepatitis B vaccine, died on 5 August 2024, at the age of 89. Pierre had his wife Irène and his son Romain close by his side through the difficult times since he had been ill. Born on 8 December 1934 in Rennes, Brittany, to pharmacist parents, Pierre remained attached to his native province, which in France is characterized by a strong anthropological particularism, throughout his life and always proudly defined himself as a Breton.

**Editor** Felicia Goodrum, The University of Arizona, Tucson, Arizona, USA

Address correspondence to Yu Wei, ywei@pasteur.fr.
The authors declare no conflict of interest.

**Published** 16 January 2025

Copyright © 2025 Bréchot et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Pierre began his medical studies in Rennes and completed his residency in hematol-
ogy, obtaining an M.D. from the University of Paris in 1968. Pierre became interested in
biology after he took a break from his career as a medical doctor to enroll in the Faculty
of Biology at Jussieu (now Sorbonne University) and learn biochemistry, a discipline he
would love for the rest of his life. Pierre began his scientific career at INSERM (French
National Institute of Health and Medical Research) in 1967 and joined the Pasteur
Institute in Paris in 1973. Convinced that molecular biology and genetic engineering,
then booming, were the key to future research, Pierre went to Cold Spring Harbor
Laboratory in the early 1970s to learn how to produce and use restriction enzymes.
He became a specialist in recombinant DNA technologies, developing the first cloning
vector derived from the lambda bacteriophage virus in 1975.

With his training in medicine, Pierre was keen to apply basic research to public
health issues. At the suggestion of his residency mentor Jean Bernard at the Saint-Louis
Hospital, Pierre turned to hepatitis B virus, whose genome was then unknown. The
story told is that knowing that Baruch Blumberg would be in transit in Paris, Pierre
went to Charles de Gaulle airport to meet the discoverer of HBV. As usual, Pierre
worked methodically and meticulously on his new research topics. Having an acute
awareness of the need for the most modern facilities, Pierre learned the set-up of a
high-security biosafety level 3 (BSL-3) facility at Uppsala University, Sweden, and built the
first BSL-3 laboratory in France at Pasteur Institute. His savoir-faire in recombinant DNA
technologies greatly advanced the pace of HBV genome cloning and sequencing in a
context of international competition, publishing with Francis Galibert the first complete
HBV genome in 1979 (1). In the same year, Pierre was appointed chief of the Genetic
Recombination and Expression Unit at Pasteur Institute, a joint laboratory of Pasteur
Institute, INSERM, and CNRS (French National Centre for Scientific Research). In the early
days of recombinant DNA, Pasteur Institute and Pierre Tiollais' laboratory, in particular,
were frequently called by other investigators to help them in their cloning projects. Such
invaluable help has been to the benefit of science in general.

The following year, Pierre's laboratory made discoveries of the presence of integrated
HBV sequences in cellular DNA of human hepatocellular carcinoma (HCC) (2), providing
a key argument for the involvement of HBV in the etiology of liver cancer. Later, his
laboratory demonstrated that oncogenic activation of cellular genes by integrated HBV
sequences *in cis* contributed to hepatocyte transformation (3, 4), giving rise to the
hypothesis of insertional mutagenesis by the virus (5). This hypothesis was particularly
validated in Pierre's laboratory in woodchuck hepatitis B virus (WHV)-induced HCC, in
which insertional mutagenesis of *myc* family genes by WHV was found in more than 80%
of tumors (6-8).

Less known, but not less significant, Pierre participated in the cloning and sequencing
of HIV and simian immunodeficiency virus at Pasteur Institute during the early outbreak
of AIDS (9, 10), making contributions to the understanding of molecular biology of this
newly identified infectious agent that was threatening the humanity.

While studying molecular biology of viruses, Pierre did not lose sight of public health
and the improvements that could be made to it with his research. Following the cloning
of HBV genome, he and his team were devoted to the development of a recombinant
vaccine against hepatitis B. While groups in the United States developed hepatitis B
vaccine expressed in yeast cells, Pierre's team chose to produce HBsAg 22 nm particles
in Chinese hamster ovary (CHO) cells for vaccine candidate (11). In collaboration with
David Milich and Francis Chisari of Scripps Clinic and Research Foundation, La Jolla,
California, they showed that the HBsAg 22 nm particles obtained from CHO cells, which
contained not only the small protein but also the middle protein of HBV envelope, are
highly immunogenic in mice, paving the way for clinical development of the vaccine
(12). The recombinant hepatitis B vaccines represent the first examples of the applica-
tion of genetic engineering to human vaccination. Since the recombinant hepatitis B
vaccine came to market in 1986, massive vaccination campaigns have been taking place
in endemic regions in the world. By one estimation, in 98 low- and middle-income
countries, 38 million deaths will be prevented due to hepatitis B vaccination among people born between 2000 and 2030 (13). Pierre was always proud to present that hepatitis B vaccines had saved lives.

Pierre possessed a sense of community and a moral commitment to sharing scientific advancement. He was one of the early organizers of the International HBV Meeting, which is still held annually. Pierre frequently visited HBV-endemic regions in Africa and South-East Asia. He was the best-known ambassador of genetic engineering, HBV biology, and liver cancer in China, a country with the highest number of HBV chronic carriers. His collaboration and friendship with Zaiping Li and Yuan Wang of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, had lasted for four decades.

Pierre was appointed a full professor at Pasteur Institute in 1988 and professor of exceptional class at the Medical School Lariboisière-Saint-Louis, University Paris 7, in 1991. He was the recipient of numerous prestigious prizes, including the prize of the Athéna Foundation—Institut de France, the grand prix of the Foundation for Medical Research, and the grand prix of Institut Electricity Health. He was elected member of the French Academy of Sciences in 1991, the French Academy of Medicine in 1996, and Chinese Academy of Engineering in 1998.

Throughout his life, Pierre valued informality, imbuing his laboratory with complete autonomy to his younger collaborators. He used to say "if a scientist wants to paint a wall in green, let him paint it in green." Some of these younger collaborators greatly benefited from the umbrella of his lab and the vivid scientific atmosphere before their settlement in a new remote environment. In his laboratory, fields as differing as adenovirus (14), interferon beta (15), HIV, retinoic acid receptor, and human molecular genetics shared one roof with HBV. His laboratory had produced so many scientific leaders in France that it formed the so-called "Tiollais School." Pierre considered it as one of his major achievements in his career.

Those who had the privilege of working with Pierre will remember him as a generous, unassuming, and warmhearted mentor. We will miss him.

## ACKNOWLEDGMENTS

All authors contribute to writing, review, and editing.

## AUTHOR AFFILIATIONS

## AUTHOR ORCIDs

Christian Bréchot http://orcid.org/0000-0002-2353-9362

Patrick Charnay http://orcid.org/0000-0002-3847-6042

Hugues de Thé http://orcid.org/0000-0002-1113-4472

Anne Dejean http://orcid.org/0000-0003-4778-6840

Marie-Louise Michel http://orcid.org/0000-0002-1231-845X

Pascal Pineau http://orcid.org/0000-0002-9407-1592

Pierre Sonigo http://orcid.org/0000-0003-2686-1303

<footnote n="1">¹Global Virus Network, University of South Florida, Tampa, Florida, USA</footnote>

<footnote n="2">²Ecole Normale Supérieure, PSL Research University, CNRS, INSERM, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Paris, France</footnote>

<footnote n="3">³Collège de France, Inserm, CNRS, PSL Research University, University Paris Cité, AP/HP: St-Louis Hospital, Paris, France</footnote>

<footnote n="4">⁴Inserm U933, Paris, France</footnote>

<footnote n="5">⁵Institut Pasteur, Paris, France</footnote>

<footnote n="6">⁶Sebia, Lisses, France</footnote>

<footnote n="7">⁷Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, University of Évry, Université Paris-Saclay, Evry, France</footnote>
Simon Wain-Hobson http://orcid.org/0000-0002-6406-3858

Yu Wei http://orcid.org/0000-0002-0020-6549

Jean Weissenbach http://orcid.org/0000-0001-6564-0840

REFERENCES

1. Galibert F, Mandart E, Fitoussi F, Tiollais P, Charnay P. 1979. Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in *E. coli*. Nature 281:646-650. https://doi.org/10.1038/281646a0

2. Brechot C, Pourcel C, Louise A, Rain B, Tiollais P. 1980. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 286:533-535. https://doi.org/10.1038/286533a0

3. Dejean A, Bougueleret L, Grzeschik KH, Tiollais P. 1986. Hepatitis B virus DNA integration in a sequence homologous to *v-erb-A* and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70-72. https://doi.org/10.1038/322070a0

4. de Thé H, Marchio A, Tiollais P, Dejean A. 1987. A novel steroid thyroid hormone receptor-related gene inappropriately expressed in human hepatocellular carcinoma. Nature 330:667-670. https://doi.org/10.1038/330667a0

5. Pineau P, Marchio A, Terris B, Mattei MG, Tu ZX, Tiollais P, Dejean A. 1996. A *t(3;8)* chromosomal translocation associated with hepatitis B virus intergration involves the carboxypeptidase N locus. J Virol 70:7280-7284. https://doi.org/10.1128/JVI.70.10.7280-7284.1996

6. Möröy T, Marchio A, Etiemble J, Trépo C, Tiollais P, Buendia MA. 1986. Rearrangement and enhanced expression of *c-myc* in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature 324:276-279. https://doi.org/10.1038/324276a0

7. Fourel G, Trepo C, Bougueleret L, Henglein B, Ponzetto A, Tiollais P, Buendia MA. 1990. Frequent activation of *N-myc* genes by hepadnavirus insertion in woodchuck liver tumours. Nature 347:294-298. https://doi.org/10.1038/347294a0

8. Wei Y, Fourel G, Ponzetto A, Silvestro M, Tiollais P, Buendia MA. 1992. Hepadnavirus integration: mechanisms of activation of the *N-myc2* retrotransposon in woodchuck liver tumors. J Virol 66:5265-5276. https://doi.org/10.1128/JVI.66.9.5265-5276.1992

9. Alizon M, Sonigo P, Barré-Sinoussi F, Chermann JC, Tiollais P, Montagnier L, Wain-Hobson S. 1984. Molecular cloning of lymphadenopathy-associated virus. Nature 312:757-760. https://doi.org/10.1038/312757a0

10. Chakrabarti L, Guyader M, Alizon M, Daniel MD, Desrosiers RC, Tiollais P, Sonigo P. 1987. Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses. Nature 328:543-547. https://doi.org/10.1038/328543a0

11. Michel ML, Pontisso P, Sobczak E, Malpièce Y, Streeck RE, Tiollais P. 1984. Synthesis in animal cells of hepatitis B surface antigen particles carrying a receptor for polymerized human serum albumin. Proc Natl Acad Sci U S A 81:7708-7712. https://doi.org/10.1073/pnas.81.24.7708

12. Milich DR, Thornton GB, Neurath AR, Kent SB, Michel ML, Tiollais P, Chisari FV. 1985. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science 228:1195-1199. https://doi.org/10.1126/science.2408336

13. Li X, Mukandavire C, Cucunubá ZM, Echeverria Londono S, Abbas K, Clapham HE, Jit M, Johnson HL, Papadopoulos T, Vynnycky E, et al. 2021. Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study. Lancet 397:398-408. https://doi.org/10.1016/S0140-6736(20)32657-X

14. Perricaudet M, Fritsch A, Pettersson U, Philipson L, Tiollais P. 1977. Excision and recombination of adenovirus DNA fragments in *Escherichia coli*. Science 196:208-210. https://doi.org/10.1126/science.322283

15. Weissenbach J, Chernajovsky Y, Zeevi M, Shulman L, Soreq H, Nir U, Wallach D, Perricaudet M, Tiollais P, Revel M. 1980. Two interferon mRNAs in human fibroblasts: *in vitro* translation and *Escherichia coli* cloning studies. Proc Natl Acad Sci U S A 77:7152-7156. https://doi.org/10.1073/pnas.77.12.7152