This year the biennial Frontiers in Retrovirology conference, hosted by BioMedCentral and the journal Retrovirology in Cambridge, UK, paid tribute to Kuan-Teh Jeang – founder of the conference and the journal Retrovirology, which celebrates its tenth anniversary in 2013. Jeang, who passed away in January 2013, was a leading scientist in retroviral research, particularly in the field of the disease-causing mechanisms underlying human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV). In honour of his significant contributions Frontiers in Retrovirology inaugurated the Kuan-Teh Jeang Memorial Lecture. The lecture was given by Stephen Goff, professor of biochemistry at Columbia University, USA and investigator at the Howard Hughes Medical Institute, USA.
Goff began his scientific career under the supervision of Paul Berg at Stanford University, USA, where he completed his doctoral studies on recombinant simian virus 40 (SV40) DNAs. Goff then joined the lab of David Baltimore at the Massachusetts Institute of Technology, USA to investigate the replication of murine leukaemia viruses. His current research efforts focus on the retrovirus life cycle and host restriction systems. This includes studies probing the machinery, such as restriction factors, that inhibit virus replication in embryonic stem (ES) cells – most likely to protect the genome housed in the germline against the insertion of viral RNA.
Goff reflects on Jeang’s achievements and discusses the research that has driven his own career in retrovirology and formed the basis of the first Kuan-Teh Jeang Memorial Lecture.
For those who did not know Kuan-Teh Jeang, can you tell us what made him such a prominent figure in the field of retroviral research?
Teh was an extraordinary scientist and active member of the retrovirus community. As a scientist, he was simply amazingly productive and creative. His lab generated beautiful and important results over many years. Throughout his career, he did rigorous and high-quality science on HIV-1 (emphasis on Tat) and HTLV-1 (emphasis on Tax). Beyond this, he was a superb and caring mentor to his students and fellows. He worked hard to promote their careers and direct them into productive paths – he was sincerely loved by his lab. He was extremely active in advancing the field of retrovirology, founding the hugely successful journal Retrovirology and serving as its Editor-in-Chief. He conceived and executed the Retrovirology prize for most outstanding mid-career retrovirologist, filling a void between junior and senior scientists. He was a strong advocate for science in Asia. And he was a committed family man. I would close by saying his main trademark was his wild enthusiasm; he always had enormous energy that came through in his work and his seminars.
How did you become interested in retroviruses? And what lay behind your recent decision to start working on the silencing of retroviruses in embryonic stem (ES) cells?
I started work on retroviruses when I began my postdoctoral fellowship with David Baltimore at MIT, switching from my graduate work on SV40. I felt these viruses were fascinating, complex, and because of their remarkable life cycle worthy of my full attention.
Our on-going work on silencing in ES cells was actually a continuation of a topic that was current in the Baltimore lab while I was there. Early work had shown that the murine leukaemia viruses (MLVs) were silenced in these cells, and it was a problem for gene therapy protocols attempting to deliver genes on retroviral vectors. The problem lay dormant for many years until new technologies like mass spectrometry made it possible for us to identify the components of the DNA-binding complex. I am always reviewing old problems with the hope of picking up and addressing those topics that have been forgotten or abandoned by the field.
Your lecture described specific mechanisms that led to the silencing of a particular murine retrovirus virus, as well as cellular mechanisms of broad importance. Can you highlight your principal findings?
We are working specifically to characterize the silencing of exogenous MLVs in ES cells, but we do believe the machinery we are studying will be found to play important roles in gene regulation in other settings.
We have found that the restriction factor TRIM28 is a key component, and that it is tethered to the MLV provirus at the so-called primer binding site (PBS) DNA by a zinc finger protein called Zfp809. We know that a protein called Yin Yang 1 (YY1) is also able to mediate a PBS-independent silencing, apparently through another DNA site and through a regulated interaction with TRIM28. We know that these proteins also regulate the endogenous proviruses in the genome. Many of the components are known to be generally important for transcriptional silencing, and some are going to be involved in silencing of HIV-1 in latent reservoirs.
If embryonic stem cells can effectively suppress retroviruses, why are these mechanisms not applied in other cells?
This particular machinery for retroviral silencing, like the many other restriction factors that have been recently uncovered (e.g. the APOBECs, TRIM5a, ZAP, tetherin) tend to be turned off and are only expressed when needed, often in response to interferon induction. We can guess or know that some of these have toxic or unwanted effects if expressed constitutively and in all cells. So the regulation of these systems does make sense.
How do you see the “frontiers of retrovirology” shaping up in the future?
Retrovirology is such a vast field, with interactions with almost all of modern biology, that one can only suppose that it will continue to advance on all fronts. We are likely to see advances in mechanisms of virus entry and trafficking intracellularly, in nuclear import and DNA integration, in proviral gene expression, perhaps especially in translation (including issues of codon usage and tRNA pools), and in virus assembly and budding, especially with respect to the many host factors involved. I am confident retrovirology will continue to be a guidepost for the study of the most interesting and exciting topics in all of cell biology.
Questions from Penelope Austin, Associate Editor for BMC Biology.