Dear TWiVirologists (Vince, Dick, Rich, Alan, Kathy),
Greeting from Haitao (Pronounced as “High Tall”, however, I am only 5’08” tall. J The real meaning of my name is “Ocean Wave” in Chinese). I am a big fan of TWiV, and I have listened to every TWiV episode since its first broadcast, but I am always a lurking audience until this email. I also like the weather report at the beginning of each episode, it has become a tradition of TWiV, and thus TWiV can also stand for “Today’s Weather in Virology”.
As an HBV virologist, I greatly appreciate that you guys discussed the recent finding on HBV receptor in the last episode (TWiV 210). The work done by Dr. Wenhui Li’s group resolved a long lasting question for HBV and it has a great potential to set up a “game changing” stage in the HBV research field. For over three decades, cell culture-based HBV research has been limited to transfection, because a manageable and robust in vitro HBV infection system was unavailable. Therefore, such groundbreaking work, although the HBV infectivity in NTCP-reconstituted hepatoma cells is only about 10% as it has achieved in primary hepatocytes, gives HBV virologists a big hope to further optimize the infection conditions for study of HBV biology under natural infection, and antivirals as well.
The paper published by Dr. Bert Semler’s group is also fascinating. 5’ tyrosyl-DNA phosphodiesterase (TDP2), which is shown to serve as an unlinkase for cleaving VPg from the terminus of polio RNA, may also play a role in the HBV life cycle. As you know, HBV genomic DNA, namely relaxed circular (RC) DNA, also has a protein (viral polymerase) covalently attached at the 5’ end of the minus strand through a tyrosyl-DNA phosphodiester bond. Upon infection and also during the viral DNA replication, RC DNA needs to be converted into a perfect circular DNA, called covalently closed circular (CCC) DNA, for viral RNA transcription. So, the removal of RC DNA terminal protein is a mandatory step in CCC DNA formation. Our previous work has identified a pol-free RC DNA species in HBV replication cycle, and this deproteinized RC DNA is a functional precursor for CCC DNA. We have also obtained evidence suggesting the removal of pol from RC DNA involves phosphodiesterase activity. Therefore it is of interest to find out whether HBV utilizes TDP2 to fill the “gaps” in its viral life.
Hopefully we can hear more and more HBV topics in your show. Keep up the fantastic work!
Happy Holidays! (attached please find a Santa-HBV.)
Haitao Guo, Ph.D
Dept. Microbiology & Immunology
Drexel University College of Medicine
I was taken aback by the knee-jerk reaction in TWiV 210 to the Canadian Supreme Court’s ruling that it was not a criminal offence for an HIV-infected individual not to disclose his/her status should he/she have an undetectable viral load and be wearing a condom. Sometimes, the immediate reaction to such rulings could be interpreted as a proclamation condoning non-disclosure, but this legal statement doesn’t mean that moral obligations don’t continue to exist.
I was glad to hear your opinions evolve quickly as you discussed the topic in 210, and explored many important and contentious points. Broadly speaking, we have to remember that HIV is spread by consensual adults participating in a sexual act, and at times when neither know their HIV status; that is, individuals acting in a manner that most of us would recognise as ordinary. The mere act of unintentionally transmitting HIV does not make someone a criminal. In fact it is something that a lot of ordinary, law-abiding people unknowingly do. Yet is there a convincing legal argument for obliging HIV positive individuals to disclose their status, even when they are undergoing treatment and practicing safe sex? Is there an independent moral argument for such an obligation?
I did my undergraduate in virology at the University of Glasgow, working on viral interferon regulatory factors with David Blackbourn. I completed my Ph.D in molecular virology with Tony Minson at the University of Cambridge, looking at intracellular signalling pathways induced by the binding of HSV-1 virions. In the middle of my virology career, I happened to find myself in law school, gaining a degree in international law, but my interest in virology won out and I did my post-doc with Max Essex at the Harvard School of Public Health. I remain at Harvard as an instructor focussing on HIV / HPV co-infection, and the epidemiological surveillance of antiretroviral drug resistance in sub-Saharan Africa.
I should point out that my comments relate strictly to the question raised by the legal ruling: whether it should be a criminal offence not to disclose one’s status should the HIV viral load be undetectable and a condom is used. The wilful and malicious transmission of HIV is a separate topic, and I am firmly of the opinion that those individuals should be prosecuted.
The criminalisation of HIV has fascinated me ever since the first case in my home country of Scotland in 2001. During my research, I’ve discovered that there is no consensus as to whether HIV transmission, or even the potential for HIV transmission, should be criminalised, and whether this involves invoking current laws or the creation of new legislation. There is inconsistency from country-to-country, and within the USA, from state-to-state, regarding prosecution, and under what laws, for those who have protected sex with a low viral load, and could be considered to have almost no risk of transmission. No federal law addressing these issues is on the statue book. There are a few examples of how state law has been applied in the USA to people living with HIV:
• A man with HIV in Texas is serving thirty-five years for spitting at a police officer;
• A man with HIV in Iowa, who had an undetectable viral load, received a twenty-five year sentence after a one-time sexual encounter during which he used a condom; his sentence was suspended, but he had to register as a sex-offender and is not allowed to have unsupervised contact with his nieces and nephews, and other young children;
• A woman with HIV in Georgia received an eight-year sentence for failing to disclose her HIV status, despite the trial testimony of two witnesses that her sexual partner was aware of her HIV positive status;
• A man with HIV in Michigan was charged under the state’s anti-terrorism statute with possession of a “biological weapon” after he allegedly bit his neighbour.
It’s worth asking whether the threat of prosecution prevents transmission and increases condom use? Not according to a study comparing the behaviour of high-risk individuals in Illinois (where there is a legal requirement to disclose your HIV-infected status to a partner) compared to New York (where there is no legal enforcement of such a provision).
We have to recall that people living with HIV are also victims of unwanted HIV transmission, and ask if nothing more than ignorance led to HIV being the only infectious disease to ever have been criminalised. AIDS kills ~9,500 people a year in the USA. We know that HBV is more infectious than HIV and leads to ~2,000 deaths a year. Although the sexual transmission of HCV is a controversial topic, nevertheless, it kills ~15,000 a year in the USA alone. And throughout history, long before HIV jumped the species barrier, bacterial sexually transmitted infections caused widespread morbidity and mortality, and continue to do so to some extent. Granted, the majority of these STIs can be treated and cured yet it still begs the question as to why we victimise those with HIV. STIs are sufficiently prevalent that an individual engaging consensually in unprotected sex should recognise that exposure to one or more STIs is a clear risk. There is the argument that sex cannot be truly consensual unless participants are apprised of all risk in order to make an informed decision, but where do we draw the line? If people with a low risk of transmitting HIV must disclose, does everyone with a known STI have to disclose? Do you have to disclose that you have a cold, just in case your partner has a particular susceptibility? Is this just the beginning of enforced healthcare through criminal law?
With appropriate treatment and care the prognosis of many HIV-positive patients is approaching “normal”. Virologically suppressive antiretroviral therapy can reduce the risk of HIV transmission by 96%, as shown in the HPTN 052 trial (Science magazine’s “Breakthrough of the Year” 2011). Using serodiscordant partnerships, the HPTN 052 study found, in ~800 couples where the infected partner was not receiving antiretrovirals, 27 HIV transmissions (which were virologically linked i.e. didn’t come from someone outside the couple), and in ~800 couples where the infected partner was on ARVs, 1 linked transmission. It’s believed that this single transmission occurred just after the individual started ARVs so his/her viral load had not yet been suppressed adequately.
The science is definitely strong enough to support the contention that those who are virologically suppressed are not infectious. The Swiss Government, in 2008, went as far as to cause a riot in the HIV prevention field by declaring: “an HIV-infected person on antiretroviral therapy with completely suppressed viraemia (effective ART) is not sexually infectious, i.e. cannot transmit HIV through sexual contact”. It highlights how polarised opinions are at the legislative level regarding the science of HIV transmission and its potential applicability to criminal law.
The treatment and prevention of HIV has been the biggest public health achievement of a generation, developed through the incomparable global, multidisciplinary collaborations of scientists and social scientists. However, the criminalisation of consensual safe sex, between an individual with a suppressed viral load and an uninfected partner, could radically undermine these achievements. It may even have the opposite effect: if the potential for transmission is, or remains, criminalised (i.e. it’s a criminal offence not to disclose your status) those who might be infected may be deterred from testing so that they spare themselves actual knowledge of their positive status. This creates a moral hazard where an infected person avoids getting an HIV test and subsequently transmits HIV, yet may not be criminally negligent as he/she had no prior knowledge of being HIV-infected.
This is exactly where all the public health progress in HIV prevention begins to unravel: 20% of HIV infections in the USA are in those who are unaware of their status, but we know that this sub-population are responsible for half of all new onward transmissions. From a public health perspective, there is no benefit to be gained from the potential, actual, or threat of criminal penalisation of the other 80%. We have to ask if society is misdirecting public resources to enforce biased, draconian legislation borne out of ignorance about a single virus? Would these funds be better directed to identifying the elusive 20% and possibly prevent half of all new infections?
I’m sure this topic will continue to stimulate a lot of heated debate, which is openly welcomed, but we have to ensure we’re disentangling the moral from the legal question: should those with an undetectable viral load engaged in consensual safe sex be criminally prosecuted for not disclosing their status? Morally, I would say “yes”; legally, “no”.
Yet, like the question as to whether viruses are alive, it may all be a matter of context.
Iain MacLeod, LL.M Ph.D
Dept. of Immunology & Infectious Diseases
Harvard School of Public Health
I am a nurse practitioner who sometimes wishes I had gotten a degree in science (with emphasis on virology/immunology) but at 50, maybe getting too old to pursue 🙂
Anyway, I would like to understand more about the function of mRNA in regards to the German scientist who claimed it could be used in production of a more efficient influenza vaccine.
Laurel, MSN, Family Nurse Practitioner
I am having some problems understanding how the triangulation number of icosahedron-shaped capsids is derived. What does it represent exactly? Trying to find answers on the internet only got me formulas to calculate T, but not a description in plain english of what it represents. I thought I understood with the lecture material of professor Racaniello on iTunesU, but was not able to put it in words or apply it to other icosahedron.
Thank you for your help,
Hey TWiV team!
I’m a graduate student at a great school, and a long time fan. I teach and I regularly suggest TWiP to my students, and I recommend TWiM to my many microbio friends (my undergrad work was in micro) to expose them to different areas of microbio in a fun, low-stress way. I know for me, you guys have been good for getting me excited about science again when grad school is really kicking my ass.
Speaking of which… I got asked to leave my lab last week. The reasons given were ones I’d heard once earlier in my career (as an undergraduate researcher) as well–“You’re so smart and so good at reading papers and synthesizing information and deeply understanding the biology… but your benchwork is so atrocious that I think you are a danger to my lab and I need you to leave.”
I’m being asked to leave my lab one year into my thesis work and two years into graduate school, with the reason being given that I’m not cut out for benchwork, either because I don’t care or because I am somehow actually mentally or physically incapable. I could choose a new lab if one will take me, but I am being advised away from benchwork strongly by my PI and they have promised to actively try to prevent labs that have any projects with live human pathogens from taking me. This largely restricts me from… all the work I came to graduate school hoping to do. I have been advised to try bioinformatics labs, which I’m not opposed to on principal, as I have a long standing interest in the human microbiome, as well as certain aspects of evolutionarily biology that are being investigated with bioinformatics techniques at my university. However, I have no training in bioinformatics, and while I’m smart and learn quickly, I would realistically require another full year of coursework to be successful in it. I find it hard to believe that anyone in bioinformatics would be thrilled to get a 3rd-year student knocking on their door because they failed at what they were actually interested in. If I choose not to find a new lab or cannot find one by November 30th, I will spend my winter quarter writing a thesis and will graduate with a master’s degree in March.
For what it’s worth, I am not completely incapable in other aspects of science–I have a published review and even the PI who is firing me says I excel at writing, reading papers, synthesizing information, and designing experiments. I also actually enjoy and am decent at teaching, and right now teaching [microbiology] parasitology is the one good thing I have left to make myself feel useful this semester. (I never thought I’d be so grateful for quizzes to grade, as painful as they sometimes are). Regardless of whether I manage to get a PhD, I don’t think I’m well suited to an academic career, because I’ve seen what it takes to make it as a young PI in this funding climate and as much as I love coming up with ideas to investigate and being involved in discovery, I have no interest in becoming that person. If I work in industry, I feel I’d probably do better in a position not requiring benchwork. Even before this happened, I was investigating my options in science communication or teaching, or maybe policy or consulting I guess.
So as I see it, here are my options. 1) I can fight to try and get into a lab that would require benchwork against the wishes of my current PI. This seems unlikely to work, but it’s possible. 2) I can fight to try and find a bioinformatics lab willing to take me, and then spend at least another 5 years on my PhD. 3) I can leave with a master’s and start now trying to get the same types of jobs I’d be after with my PhD, just without the advantage of a few more years to prepare myself for the job market and with less-impressive letters after my name.
I’m currently actively investigating options 2 and 3, and 1 to a lesser degree, following the advice of a professor I rotated with who sadly can’t take me due to budget constraints but who has been an amazing mentor.
My question to you guys is this: Given that I don’t want a research career anymore and my options for new labs are very limited, do you think the uphill battle I’d be facing to even earn the right to TRY to finish the PhD is worth the effort? It is entirely possible that I could find a place for myself in bioinformatics if given the chance, but some non-research positions could also make me equally happy, without sacrificing another 5 years in a system that has already chewed me up and spit me out. So what do you say guys? Any insight into what to do with a student who is supposedly brilliant, but useless on a practical level?
Thanks for reading,
Dear TWIV team
During episode 198 you talked about the eternal competition between viruses and their hosts: the so called “Red Queen’s race”. It occurred to me that the character of the race must have changed when animals evolved sufficient intelligence to know to avoid sick (and therefore infectious) neighbours. Would this have put selective pressure on viruses to either not produce visible symptoms of disease, or to take a long time about it in order to provide a window in which their host could infect others?
For humanity, a much more important change to the nature of the race must have happened in the last two hundred years. Our increasing intelligence has got us to the point where, unique among all the species on this planet, we are actually aware of viruses’ existence, and we use our intelligence to develop treatments against them.
From this perspective it might not be too much of an exaggeration to regard Virologists as an evolved response to the problem of viruses. (We must hope that viruses don’t retaliate by selectively targeting Virologists.)
More seriously, given the extra effort that humans are making to defeat viruses that infect us and those species dear to us, are there any signs that these viruses are now evolving faster than viruses that aren’t in our sights?
Please keep up the great work with all your podcasts. I now listen to TWIV, TWIM and TWIP, even though I’ve had to increase the number of times a week I go to the gym to find time to listen to them all.
Yours ever gratefully
Thought you would enjoy this piece on the future of bio-design. The handle “Cap’n Capsid” is pretty fun. Oh my.
Best to you all,
Neva From Buda
Hacking the President’s DNA
by Andrew Hessel, theatlantic.com
October 25th 2012
Original Page: http://pocket.co/sdJ96
My name is Barbara and I’m a student from University Fernando Pessoa in Porto, Portugal. First of all I would like to apologise for my English…It’s not perfect!!!
I’m a reader and listener from your website and podcasts, which I appreciate a lot. I’m now on the last year of my course on pharmaceutical sciences and I’m starting my final project.
My project theme is about: Virus as machines in pharmaceutical sciences.
When I thought about it, I’ve had some ideas such as: vaccines, gene therapy, virus in bacteria, biotechnology (for example is it possible to introduce some genomic material of virus in food that with metabolic processes would be introduced in our genome in order to fight some diseases?). In synthesis, how could virus be more useful to develop new drugs?
The purpose of this e-mail is to ask you, if you could give me some more ideas so that I can develop my project correctly and if possible, sending me some reading material about this theme and these sub themes.
Thank you very much.
In the introduction you say “the kind that make you sick”.
We should also acknowledge all that retroviruses do for us. They (or their remnants in the human genome) literally keep us going. Metabolic processes essential to us depend on them. Even the continued existence of all placental mammals depends on the syncytin gene co-opted from some ancient friend to make the syncitiotrophoblast of our placentas.
While the disruptive effects of the viruses are more readily recognised, their beneficial effects working quietly in the background are harder to detect.
In a very real sense, “Viruses ‘R Us”.
Perhaps the introduction should be “the kinds that make you and the kinds that make you sick”.
Love your podcast.
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