Archive for the ‘Vaccines: General’ Category

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Virus structure visualisation – from here at home!

23 June, 2011

I was most pleased to discover via their blog that two of my colleagues here at UCT – Andrew Lewis and Timothy Carr, who do High Performance Computing support – have (a) been taking a more than passing interest in implementing some quite serious bioinformatics support (see Mr Bayes as well), and (b) doing visualisations of nasty virus proteins, just because they could!

Here is one for an Ebola virus protein, and here is another for Lujo virus, also covered quite extensively here.

And I liked it enough I stole it…B-)

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Measles just won’t go away

6 June, 2011

I have written before in ViroBlogy about measles resurging in Africa (see: Measles in Zimbabwe from January 2010) – and now Larry Madoff, the Editor of the very worthy ProMED, makes the case that it is resurging all over.  And in the case of developed countries, largely because of simple stupidity.

From Larry:

Once nearly eradicated in much of the developed world, measles outbreaks are becoming more frequent in 2011. They are the result of increased global travel, lower rates of vaccination in poorer counties – and parents choosing not to vaccinate their children in the U.S., Europe and elsewhere [my emphasis] because of the now widely discredited myth that the measles, mumps and rubella vaccine causes autism.

Whenever people are on the move, there are risks of infectious diseases moving with them.

… [ fundraising message removed: go here to donate]

Measles kills an estimated 165,000 people each year, mostly in poor countries. Since January, however, measles outbreaks reported on ProMED mail have occurred not only in poorer nations such as Bangladesh, Somalia, and Pakistan, but in such countries as France, Spain, England, Canada, Australia, New Zealand, and within the U.S. from Massachusetts to Utah, Minnesota to New Jersey. An outbreak of measles in the Canary Islands and several South American countries, in fact, appears to be the result of unvaccinated British and German tourists bringing the disease to their shores.

As I said, then: stupidity, in the case of unvaccinated tourists.  And lack of vaccine or problems in delivery in the case of the poorer nations.

The first is easy to fix: simply don’t let any tourists in without proof of measles vaccination, as presently happens in Brazil for yellow fever, for example.  It would be done for all the wrong reasons, but hey, whatever works!

The second…is harder.  Measles vaccines are good: they are effective and safe, whether given singly or in combination (eg: measles-mumps-rubella; MMR) – and pretty cheap; cheap enough to be included in the free Extended Programme of Immunisation (EPI) bundle in many countries.  But the simple fact is that they are not getting to many of the folk who need them – and given that you need a minimum of 80% coverage to get “herd immunity”, the virus just keeps on being transmitted around.

And measles is not a trivial disease, whatever the lay population thinks: if it can kill or cause severe complications in healthy, well-fed children, imagine how much worse the consequences of infection are in malnourished, sickly children. As mentioned above, 165 000 people – and mainly children – die every year from measles.

From the WHO Measles Fact Sheet:

Measles is a highly contagious vaccine-preventable disease caused by the measles virus, a member of the genus Morbillivirus in the family Paramyxoviridae. It is spread by droplets or direct contact with nasal or throat secretions of infected persons; less commonly by airborne spread or by articles freshly soiled with secretions of nose and throat. Measles is one of the most readily transmitted communicable diseases and probably the best known and most deadly of all childhood rash/fever illnesses. [my emphasis].

The scale of the problem can be seen here:

Anywhere that isn’t blue has less than 90% coverage – and look at Africa…mostly 50-79% coverage, and that is simply not enough.

Look again at the complications of natural measles infections – from the CDC Measles Complications page:

About 30% of measles cases develop one or more complications, including

  • Pneumonia, which is the complication that is most often the cause of death in young children.
  • Ear infections occur in about 1 in 10 measles cases and permanent loss of hearing can result.
  • Diarrhea is reported in about 8% of cases.

These complications are more common among children under 5 years of age and adults over 20 years old.

Even in previously healthy children, measles can be a serious illness requiring hospitalization. As many as 1 out of every 20 children with measles gets pneumonia, and about 1 child in every 1,000 who get measles will develop encephalitis. (This is an inflammation of the brain that can lead to convulsions, and can leave the child deaf or mentally retarded.) For every 1,000 children who get measles, 1 or 2 will die from it. Measles also can make a pregnant woman have a miscarriage, give birth prematurely, or have a low-birth-weight baby.

In developing countries, where malnutrition and vitamin A deficiency are common, measles has been known to kill as many as one out of four people. It is the leading cause of blindness among African children. [my emphases]

Sub-acute sclerosing panencephalitis (SSPE) is a very rare, but fatal degenerative disease of the central nervous system that results from a measles virus infection acquired earlier in life. Analysis of data from an outbreak of measles in the United States during 1989-1991 suggests a rate of 4-11 cases of SSPE per 100,000 cases of measles. A risk factor for developing this disease is measles infection at an early age.

If this doesn’t scare you, then you are invincibly ignorant.  Or simply stupid.  Which the Bill & Melinda Gates Foundation is not – they have supported new measles vaccine development since 2000; they are also recently involved along with the Lions Club International Foundation in the Measles Initiative, which is:

“…a worldwide effort to protect children from measles and strengthen routine immunization services. UNICEF, World Health Organization (WHO), U.S. Centers for Disease Control (CDC), American Red Cross, and the United Nations Foundation are among the organizations contributing to these efforts since 2001.”

From their site:

An estimated 164,000 people – 450 a day – died from this easily preventable disease in 2008. Costing less than US $1 to vaccinate a child, the measles control strategy represents one of the most cost-effective health interventions available.

Yet, many developing countries that are facing multiple health challenges have limited funds, making financial support from the Measles Initiative critical. A steep decline in donor investment has resulted in a significant funding gap. Unless conditions improve, the shortfall will put the goal and millions of children at risk.

We can eradicate measles.  We really, really can – but it starts with vaccinating your children, and yourself.  Then helping vaccinate others.

 

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Prune(lla) juice shall set you free

25 May, 2011

I couldn’t resist that title, even though it has a qualifier for the sake of correctness: it stems from South African graffiti from the 1970s or so (collected into a book by Arnold Benjamin), and I was irresistibly reminded of it by a paper recently published in Virology Journal.  Of course, it is a pity that Prunella vulgaris is in fact a mint, and not a stone fruit, but there you go.  Yet more evidence that herbal extracts can act against viruses – and in this case, against one that really, really does does need some antagonists.

Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L.

ChoonSeok Oh, Jason Price, Melinda A Brindley, Mark P Widrlechner, Luping Qu, Joe-Ann McCoy, Patricia Murphy, Cathy Hauck and Wendy Maury*

Virology Journal 2011, 8:188 doi:10.1186/1743-422X-8-188  Published: 23 April 2011

Background

The mint family (Lamiaceae) produces a wide variety of constituents with medicinal properties. Several family members have been reported to have antiviral activity, including lemon balm (Melissa officinalis L.), sage (Salvia spp.), peppermint (Mentha × piperita L.), hyssop (Hyssopus officinalis L.), basil (Ocimum spp.) and self-heal (Prunella vulgaris L.). To further characterize the anti-lentiviral activities of Prunella vulgaris, water and ethanol extracts were tested for their ability to inhibit HIV-1 infection.

Results

Aqueous extracts contained more anti-viral activity than did ethanol extracts, displaying potent antiviral activity against HIV-1 at sub μg/mL concentrations with little to no cellular cytotoxicity at concentrations more than 100-fold higher. Time-of-addition studies demonstrated that aqueous extracts were effective when added during the first five hours following initiation of infection, suggesting that the botanical constituents were targeting entry events. Further analysis revealed that extracts inhibited both virus/cell interactions and post-binding events. While only 40% inhibition was maximally achieved in our virus/cell interaction studies, extract effectively blocked post-binding events at concentrations similar to those that blocked infection, suggesting that it was targeting of these latter steps that was most important for mediating inhibition of virus infectivity.

Conclusions

We demonstrate that aqueous P. vulgaris extracts inhibited HIV-1 infectivity. Our studies suggest that inhibition occurs primarily by interference of early, post-virion binding events. The ability of aqueous extracts to inhibit early events within the HIV life cycle suggests that these extracts, or purified constituents responsible for the antiviral activity, are promising microbicides and/or antivirals against HIV-1 [my emphasis].

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Should remaining stockpiles of smallpox virus be destroyed?

19 April, 2011

Our Department has a journal club every Friday, when research folk (staff and students) get together to hear a postgrad student present an interesting new paper.  Last Friday Alta Hattingh from my lab gave a thought-provoking and insightful presentation on whether or not smallpox virus should be destroyed – so I asked her to turn it into a blog post.

Should remaining stockpiles of smallpox virus (Variola) be destroyed? 

Raymond S. Weinstein

Emerging Infectious Diseases (2011), Vol 17(4): 681 – 683

Smallpox virus replication cycle. Russell Kightley Media

Smallpox virus replication cycle. Russell Kightley Media

Smallpox is believed to have emerged in the Middle East approximately 6000 to 10 000 years ago and is one of the greatest killers in all of human history, causing the death of up to 500 million people in the 20th century alone.  Smallpox is the first virus to ever be studied in detail and it is also the first virus for which a vaccine was developed.  Smallpox was beaten by the Jenner vaccine (first proposed in 1796) and the disease was declared eradicated in 1980 in one of the greatest public health achievements in human history.

The last officially acknowledged stocks of variola are held by the United States at the Centres for Disease Control and Prevention (consisting of 450 isolates) and in Russia at the State Research Centre of Virology and Biotechnology (various sources place the number of specimens at ~150 samples, consisting of 120 strains).  This includes strains that were collected during the Cold War as potential for biological weapons due to their increased virulence. Then, there is also the added possibility that stolen smallpox cultures are in the hands of terrorists organizations.

In 2011 the World Health Organisation (WHO) plans to announce its recommendation for the destruction of all known remaining stockpiles of smallpox virus.  They have wanted to destroy the virus ever since 1980 when the Secretary of Health and Human Services, Louis Sullivan, promised destruction of US stockpiles within 3 years. This never happened in the US or Russia and no official recommendation for destruction have been recommended by the World Health Assembly.  In 2007 the final deadline for a decision was postponed until 2011 as no consensus could be reached among the executive board of the WHO.

The only real benefit that could be gained from destroying all known remaining stockpiles of smallpox virus in the world would be the prevention of causing a lethal epidemic due to theft or accidental release of the virus.  However, according to Weinstein destruction would only provide an illusion of safety and that the drawbacks of eliminating variola from existence are many.

In this paper Weinstein mentions the possible reasons behind the hesitance to destroy smallpox.  The prolonged existence of smallpox along with the important clinical implications of its high infectivity and mortality rates suggests that the human immune system evolved under the disease’s evolutionary influence.  In the last decade research has been done which suggests that variola (and vaccinia) have the ability to alter the host immune response by targeting various components of the immune system.  We are only beginning to understand the complex pathophysiology and virulence mechanisms of the smallpox virus.  An example of the importance of smallpox in human evolution is the CC-chemokine receptor null mutation (CCR5Δ32), which first appeared in Europe ~3500 years ago one person and today it can be found in ~10% of all those from northern European decent.  The mutation prevents expression of the CCR5 receptor on the surface of many immune cells and provides resistance to smallpox.  This same mutation also confers nearly complete immunity to HIV. In a recent study done by Weinstein and co-workers (2010) it was postulated that exposure to vaccinia and variola may have previously inhibited successful spread of HIV, suggesting that we swopped out one major disease for another. By eliminating the variola stockpiles from existence on-going research in this direction might be hampered and the possibility future studies employing intact virus will be rendered impossible.

Finally, we are capable of creating a highly virulent smallpox-like virus from scratch or a closely related poxvirus through genetic manipulation.  This renders moot any argument for the destruction of remaining stockpiles of smallpox in the belief that it would be for the benefit of protecting mankind.

In an editorial of the Vaccine journal, the editors make a compelling case in favour for the destruction of remaining stockpiles of smallpox virus.    To follow is their take on the situation:

Why not destroy the remaining smallpox virus stocks?

Editorial (by J. Michael Lane and Gregory A. Poland)

Vaccine (2011), Vol 29:  2823 – 2824

The Advisory Committee on Variola Virus Research (created in 1998 as part of the WHO) concluded that live variola is no longer necessary except to continue attempts to create an animal model which might mimic human smallpox and assist in the licensure of new generation vaccines and antivirals.

The editors feel that scientific recommendation for keeping smallpox stocks need to be scrutinized and that a number of political and ethical issues need to be addressed.  Below are comments by editors on these issues:

Scientific issues:

The smallpox virus is no longer needed to elucidate its genome, 49 strains have been sequenced and published, the editors feel that there is no need to sequence additional strains.  The smallpox virus can be destroyed as it is possible to reconstruct it from published sequences or to insert the genes of interest into readily available strains of vaccinia or monkeypox.  Refinements regarding diagnostics can be made by using other orthopoxviruses or parts of the smallpox strains already sequenced; vaccines have been produced that are far less reactogenic than the first and second generation of vaccinia vaccines and they are very effective against other orthopoxviruses.  Finally, the development of an animal model is difficult to perfect as variola is host-specific, thus there are no guarantees that a model will be found that mimics the pathophysiology of smallpox in humans.

Political/ethical issues:

The US is a supporter of the WHO and the UN and failure to comply with the request of the World Health Assembly jeopardizes the US’s potential to work with the UN to further their foreign policy and population health goals.  Biological weapons have been banned from the US military arsenal and there is no way they would use a biological weapons such as smallpox whether it be in offense or defence.  The editors reckon that the risk of a biological warfare attack using smallpox is highly unlikely as terrorists who have the knowledge and sophistication to grow and prepare smallpox for dispersal would realize that they could cause harm to their own countries.  Apart from that, Western nations have the facilities to isolate and vaccinate against smallpox in a timely manner.

According to the editors there is no ethical way to justify maintaining an eradicated virus.  Even though the possibility of accidental release is very small, it is an unacceptable risk.  Maintenance of the smallpox virus stocks is expensive and time consuming, it also burdens the CDC without scientific merit and their resources are better used to protect the public from infectious diseases.

In conclusion the editors maintain that the remaining smallpox stocks should be destroyed and the world should make possession of the virus an “international crime against humanity”.

We are presented with two very different views with regards to whether or not smallpox virus stocks should be destroyed forever.  The WHO meets again this year to decide the final fate of smallpox. Will the board reach consensus or will the smallpox virus yet again receive a stay of execution? 

Note added 1 Oct 2015

Interestingly, I found the following text written by me in my archive of articles – published as a Letter in the now sadly defunct HMS Beagle, in 1999:

HMS Beagle

( Updated May 28, 1999 · Issue 55) http://news.bmn.com/hmsbeagle/55/viewpts/letters

Use logic, not fear

The destruction of all (known) stocks of smallpox virus (Reprieve for a Killer: Saving Smallpox by Joel Shurkin) seems to be a very emotive issue. Perhaps, if people looked at it less in terms of a threat, and more in terms of a resource, most of the problem would go away. For example, although the original article made mention of monkey pox, and how it was almost as dangerous as smallpox, and appeared to be adapting to human-to-human spread, nothing has been said about investigating why smallpox was so much more effective at spreading within human populations than monkey pox is. It is all very well having the smallpox genome sequence; however, without the actual DNA, it is difficult to recreate genome fragments of the size that may be needed to make recombinant viruses to investigate the phenomenon of host/transmission adaptation. Additionally, without the actual virus, it will be impossible to compare the effects of a doctored vaccine strain with the real thing. Destroying known stocks of the virus will not affect the stocks that are most likely to be used for bioterrorism. It will, however, handicap research into ways of combating the virus/understanding how it worked in the first place.

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Posted in biotechnology, Evolution, General Virology, history, Vaccines: General, Viruses | 8 Comments »

What are you looking for?

18 April, 2011

It is quite educational sometimes, to look and see what it is people are looking for, when they end up on ViroBlogy.  Here are the queries over the course of the last month:

Search Views
ebola 577
ebola virus 64
rolling circle 44
how did viruses evolve 29
mimivirus 21
despair posters 19
flaviviridae 17
lassa fever 14
bacterial dna replication 11
ebola virus patients 11
viroblogy 9
where did viruses evolve from 9
ebola pictures 9
rift valley fever 9
what did viruses evolve from 9
geminivirus 8
west nile virus structure 8
ebola patient 8
where h1n1 came from 7
ebola virus pictures 7

I count 6 mentions of Ebola, 4 of virus evolution generally…and a gratifyingly high number of queries on rolling circle replication, given our lab’s interest in it.  Of course, I have had long had an obsession with Ebola and similar nasties, and have been deeply interested in the evolution of viruses ever since I started studying them, so it is good to see others share my interests!

So in the spirit of giving people what they want, look for blog posts with titles like “The evolution of viruses using rolling circle replication: its complete non-relevance to Ebola and H1N1 influenza viruses”.  But seriously – I will be putting up some more posts around the most popular subject areas, if only to help make sure that The Truth Gets Out There.

Ed Rybicki

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Posted in Evolution, General, General Virology, Influenza viruses, Viruses | 3 Comments »

InCROIable quatre!

3 March, 2011

This morning, I’m afraid I experienced rather more secondary effects from the previous night’s entertainment. Thanks to my friend Sylvie, I got invited to the Walker lab party, where I found myself hopelessly outclassed, both scientifically and alcoholically*. Over the course of the evening, I’m sure we worked out exactly how to both cure HIV infection, and produce an effective vaccine, but by the time I awoke (somewhat disorientedly) this morning, it had all disappeared in a mist of Sam Adams.

XMRV – the incredible vanishing virus

As you may recall, in 2009 a new retrovirus called XMRV was reported to be associated with chronic fatigue syndrome (CFS – Lombardi and colleagues 2009). It had previously been reported to be associated with prostate cancer. These results have been the subject of much controversy, and today there was a one-hour discussion session on XMRV. Speakers gave two-minute presentations of their recent results, and this was followed by comments from the floor. The highlights were as follows:

Four different labs, using different techniques reported that they basically did not find XMRV in humans.

William Switzer (CDC, USA) – Tested 45 CFS patients and 42 controls using the same technique as that reported in the Lombardi paper, and looked for serology by Western blot. ZERO POSITIVES.

Timothy Henrich (Brigham and Women’s Hospital, USA) – Tested 293 diverse and varied patients, and 3 CFS patients reported to be XMRV positive in a previous study by nested PCR. ZERO POSITIVES.

Mary Kearney (NCI Frederick, USA) – developed a quantitative PCR assay with single-copy sensitivity to detect XMRV. Reported experimental infection in two macaques. In those two animals, XMRV proviral DNA persisted in blood cells, and was consistently detected. Using this technique, they tested 134 prostate cancer patients, and 4 patients previously reported as XMRV positive in the Lombardi study. ZERO POSITIVES.

Finally, Oya Cingoz (Tufts, USA) and Vinay Pathak (NCI Frederick, USA) reported on the origins of XMRV. This virus was first described in a protstate cancer cell line called 22Rv1, which secretes XMRV. This cell line definitely carries the virus, but how did it get there?

Like many immortalized cell lines, 22Rv1 started out as a human tumor transplanted into immunodeficient “nude” mice in what is known as a xenograft. It was passaged in this way many times in different types of mouse – suggesting that 22Rv1 may have acquired XMRV from its mouse hosts. This is plausible because mice carry many types of endogenous retroviruses in their genomes. Cingoz and Pathak showed that althoug XMRV is not identical to any known mouse retroviruses, the left-hand (5′) half of XMRV is identical to one particular mouse retrovirus, while the right-hand (3′) half is identical to a different mouse retrovirus. XMRV is therefore a new virus produced by recombination between two distinct mouse viruses. This all happened since 1992, when the prostate cancer that gave rise to 22Rv1 was first transplanted into nude mice. It is not a virus that has been circulating in human beings.

One would have liked to have heard the other side of the story from the authors of the Lombardi paper, but they didn’t show up to face the data. I guess that tells its own story.

So just to wind up, XMRV is NOT associated with CFS, and does not appear to be present in the human population (although one might wonder whether researchers working with the 22Rv1 line might in fact be at risk of infection).

If you have CFS, do not buy a test for XMRV (they are entirely BOGUS, as Simon Singh might have said), and do not ask your doctor for antiretroviral medication (unless you are HIV positive, of course). It will be a waste of money, and you will just get the side effects of the medication, without any benefit.

And that was it for the 18th CROI!

Dorian

* OK, maybe only scientifically

…and my thanks, Dorian, for a job really well done! – Ed

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Posted in General Virology, HIV, Vaccines: General | 22 Comments »

InCROIable trois…

2 March, 2011

Going into day 3, and the only ill effect carried over from last night’s French AIDS research party is a mild ringing in the ears from ANRS director François Delfraissy’s experiments with audio feedback, while he was thanking us all for our efforts. Next time, please don’t stand so close to the speakers when you’re talking into the microphone, Professor Delfraissy!

One of this morning’s plenary talks was from Stephen Cherepanov, on the structure of the HIV integrase complex, but since this has already been covered in Viroblogy, I don’t need to say any more about it. Rather fortunately, because describing the 3-D structures of the integrase-DNA complex would have been far, far beyond my literary prowess. “Yes, well, try to imagine a couple of short tube-shaped sections, close together, but held at an angle – not parallel to one another. Those are the ends of the proviral DNA, just before strand-transfer. They’re being held in place by what looks something like a Henry Moore sculpture, and the wiggly orange bit, close to one end of short tube-shaped DNA ends – that’s the active site of the enzyme.” You see what I mean?

Anyway, later on there was a session on HIV-host cell interactions, one of which harked back to those pesky microRNAs from the other day. Carlos de Noronha (Albany Med Coll, USA) told a story that led from Vpr – one of the HIV’s small proteins – to micro RNA. Vpr has several effects on infected host cells, including cell cycle arrest (infected cells stop dividing) and inducing expression of molecules on the surface of the infected cell that prevent infected cells being killed by “Natural Killer” cells of the immune system. The way Vpr does this, apparently, is by interacting with a ubiquitin ligase complex (DECAF1-CRL4). Ubiquitin ligases stick a protein called ubiquitin onto other proteins, and this ubiquitin tag marks its victim for destruction. De Noronha’s group set out to identify what other cellular proteins are ubiquitinylated by DECAF1-CRL4, and could therefore be influenced by Vpr. Their hunt turned up Dicer, which is involved in producing miRNAs. They showed that Vpr does indeed induce DECAF1-CRL4 to tag Dicer for degradation, and that viruses deficient in Vpr replicate efficiently  only when Dicer is artificially depleted. Now it’s not at all clear why destroying Dicer is useful for the virus, but in answer to a question, de Noronha suggested that infected cells may use miRNA to shut down expression of host factors necessary for HIV replication. In that case, it would be useful for HIV to block production of cellular miRNA.

Micro RNA came back again in the afternoon when Mary Carrington (NCI Frederick) presented data in press in Nature dissecting an association between a genetic polymorphism in HLA-C, and control of HIV infection. The HLA region of the genome controls, to a large extent, the immune response against infectious diseases, including viruses. It is also extremely polymorphic (that is, variable between individuals) and this polymorphism is what ensures that the human race would not be entirely wiped out if an extremely nasty, new infection were to appear. Because of the variability in the immune response between individuals, no virus can be perfectly adapted to every individual in the whole population. Variations in HLA-B genes modify the HLA-B proteins, and this alters their ability to present HIV epitopes, which in the end results in people with certain HLA-B variants (or alleles) such as HLA-B57 and B27 controlling HIV infection better.

The HLA-C polymorphism associated with control of HIV infection, however, does not alter the HLA-C protein, so until this afternoon, it has been rather mysterious how it might work. Well, to cut a long story illustrated by several slides short, it turns out that the protective HLA-C alleles have modifications in the 3′ non-coding region of the gene, and these changes occur in a microRNA (miR-148) binding site. In variants which can be targeted by miR-148, the level of HLA-C expression on the surface of cell are lower. Variants associated with better control of HIV infection “escape” from miRNA148 control, and result in higher HLA-C expression. Moral of the story – even “silent” gene polymorphisms can in fact be functional, and rather strangely, it appears that avoiding control by microRNA can be a mechanism of host defence as well as a means of virus attack.

Also, a very interesting talk from David Evans (Harvard, USA) about how different primate lentiviruses avoid being retained on the surface of the infected cell by Tetherin. One interesting point that he illustrated was that HIV-1 type M viruses are much better at escaping from Tetherin’s grip than HIV-1 type O and type N viruses. This could be one reason why HIV-1 type M viruses are more infectious, and why they, rather than the other two types of HIV-1, caused the current HIV pandemic.

Dorian

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InCROIable Deux

1 March, 2011

In which the redoubtable Dorian reports further on the doings at CROI 2011.

Neutralizing HIV

Michel Nussenzweig (Rockefeller, USA) gave everyone an immunology lesson in order to explain what makes broadly neutralizing anti-HIV antibodies so special. So carrying on with the immunology lesson theme, I should just point out that neutralizing antibodies are those that not only stick to the surface of a virus, but actually prevent it from infecting a susceptible cell. So far, all effective antiviral vaccines work because they can induce these neutralizing antibodies. So that’s what neutralization is, now where does the “broadly” part come in? HIV is of course a highly variable virus, so “narrowly” neutralizing antibodies only neutralize a small number of HIV variants, while “broadly” neutralizing antibodies can block infection from a wide range of different HIV variants.

To date, none of the HIV vaccine candidates tested has been able to induce broadly neutralizing anti-HIV antibodies effectively, and most HIV-infected people do not make this type of antibody during natural infection. However some people with HIV infection do produce broadly neutralizing antibodies (It should be stressed however, that HIV+ individuals who make broadly neutralizing antibodies are not cured of their infection). The reason for studying antibodies from such people is that if we can understand how broadly neutralizing antibodies are formed during natural infection, then perhaps we might find a way to induce the same kind of antibodies with a HIV vaccine.

Using a variety of fantastically ingenious techniques, Nussenzweig showed us that the magical processes of hypermutation and affinity maturation are essential for the potency and the breadth of broadly neutralizing anti-HIV antibodies. These processes occur in the germinal centres of lymph nodes, and he presented some amazing imagery data to show that the maturation of antibodies is controlled by the CD4+ T-cells in the germinal centre that “help” B-cells produce antibodies. So the final message, I guess, is that CD4+ T-cell responses are going to be essential for a vaccine to be able to induce a good neutralizing antibody response.

However, that still doesn’t resolve the “broad” part of the problem – how to focus the antibody response onto the sensitive parts of the virus. Indeed, as a presentation in the afternoon from Laurent Verkoczy (Duke Univ. USA) showed, this may be extremely difficult to achieve. For one broadly neutralizing epitope on HIV (the so-called MPER epitope), the antibodies that bind to this site on the virus are also auto-reactive. In a mouse model, he showed that the cells that carry these antibodies are “strangled at birth” by the mechanisms that prevent our immune system from damaging ourselves. These antibodies have therefore probably been deleted from most people’s immune repertoire, and are therefore not available to be selected and amplified by vaccination.

So I’m afraid no-one has yet found the way to induce these broadly neutralizing antibodies.

A virus that slows down HIV

GBV-C is a virus infecting humans that is transmitted by sex, blood transfusion, and from mother to child – rather like HIV. It is a flavivirus (other family members include yellow fever virus, and hepatitis C virus), and because of its mode of transmission, GBV-C is often found in HIV seropositive people. It does not seem to cause disease in people who are infected either acutely, or chronically. Now, you might expect that being infected by two different viruses at the same time would be worse than just being infected by one. But remarkably, the 20-40% of HIV+ individuals who have chronic GBV-C infection have SLOWER disease progression than those who only have HIV infection (at least in European/North American patient cohorts).

There were two talks presenting results trying to explain this intriguing observation. Molly Perkins (NIAID, USA) presented data from a study of HIV-infected patients in the Gambia. She found that GBV-C coinfection did not change T-cell activation, but reduced expression of the HIV coreceptor CCR5 on T-cells. In direct contrast to these results, Jack Stapleton (U Iowa, USA) presented data showing the exact opposite. In his study, GBV-C lowered T-cell activation, but had no effect on CCR5 expression.

How can two groups looking at the same question get such discordant results? Jack Stapleton noted that the different studies on this topic have been conducted in different regions of the world. Both HIV and GBV-C show geographical variation – that is to say, the HIV that infects people in Iowa is not the same as the HIV that infects people in the Gambia, and the same goes for GBV-C. So one plausible explanation may be that different types of GBV-C have different biological effects.

Not wanting to send the room into an uproar, I didn’t ask the question that immediately sprung to my mind – when are we going to test GBV-C infection as a therapeutic intervention?

Dorian
Lecturer in Microbiology, University of Nantes

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InCROIable…Dorian McIlroy reports

28 February, 2011

The penalty for winning a competition here on ViroBlogy is writing an article for ViroBlogy – 2nd prize would, of course be writing TWO articles.  Mind you, as two-time winner, regular commenter Dorian McIlroy gets to do just that.  He has volunteered to report daily from CROI 2011, the 18th Conference on Retroviruses and Opportunistic Infections in Boston, that’s on right now.  Thanks Dr D!

“So here I am in the snow in Boston at the 18th CROI. The opening talk is from Bryan Cullen (Duke, USA) on viruses and micro RNA, known as miRNA. As readers may know, there are three main functions types of RNA inside cells. Messenger RNA (mRNA) is the intermediate between a sequence of DNA and the protein that the DNA sequence encodes. It carries the message, so to speak, telling the protein synthesis machinery what protein to make.  The two other main types of RNA (tRNA and rRNA) are involved in the translation of the mRNA message into protein.

However, in addition to these common or garden types of RNA, cells also produce very small RNA molecules, that do not code for proteins, and are not directly involved in protein synthesis. So what are they for? Well, we will have to wait till Prof. Cullen tells us. Right now, John Coffin (Tufts, USA) is giving the opening talk. There are about 4000 delegates, all lined up in a big auditorium. As you can imagine, the speaker is a little tiny blob at a lectern way, way up at the front. Fortunately, the
speaker’s head and torso is projected on a big screen at the same time.  The films of all the talks are available on the CROI website (www.retroconference.org), which kind of defeats the purpose of  my writing these blog posts I guess…..[NO!  Ed]

But  on with Bryan Cullen. miRNAs are expressed in all multicellular organisms. There are over 1000 of these miRNAs in humans, and their role is to regulate mRNAs – so in fact they control gene expression. In plants and insects, some miRNAs have anti-viral functions, but this is not the case in mammals. In fact, at least one human virus (HCV) uses a host cell miRNA for its own replication.

In addition, some DNA viruses – mostly herpesviruses – also code for miRNAs. One of these is Epstein-Barr Virus (EBV) which is associated with several cancers. When EBV infects B-lymphocytes from the blood, these cells grow in an uncontrolled way (that is, they become pre-cancerous).   It turns out that only one of the EBV miRNAs (BHRF1-2 if you really want
to know) is involved in turning normal B-cells into pre-cancerous cells.  Dr Cullen then goes on to explain an interesting technique called “PAR-CLIP” that allows you to identify the target genes of a particular miRNA, and gives us a list of the cellular genes targeted by  BHRF1-2.

Take-home message – some oncogenic DNA viruses use miRNAs to manipulate host cell biology, and this is involved in their ability to induce cancer.

This is followed by a harrowing story from Fred Hersch, of his own brush with death due to HIV/AIDS. Fortunately, he survived, due to the extraordinary efforts of the ICU at St Vincent’s hospital in New York, and is now playing piano for us all.

After the musical interlude, Anthony Harries (now at the International Union against TB and kung diseases in Paris) gives an excellent talk (hey – not that the first talk wasn’t excellent too) describing his time as head of HIV/AIDS health care in Malawi. He was there when HIV seroprevalence rose from less than 1% to about 15% in the adult population. For several years in the 1990s and the beginning of the century, no treatment was available to stop people from dying. During that
period, 90% of patients diagnosed with stage 4 AIDS were dead one year later. That began to change, he says, with the world AIDS conference in Durban in 2000, where international efforts to make antiretroviral therapy (ART) available in sub-Saharan Africa began to take shape. He then goes on to explain how ART is implemented in Malawi – and shows how coffin sales in one district have plummeted over the last few years. This is the real clinical success of making ART available – the decade-long wave of deaths has abated.

That was the good news. Now for the bad news. Transmission rates are still high – with an estimated 70 000 new HIV infections in Malawi each year. So the HIV problem has certainly not gone away, it has just been contained.  Secondly, current guidelines for starting ART depend on a HIV+ individual’s CD4+ T-cell count, and if you don’t have the means to determine the CD4 count (of the 400 ART centres in Malawi, only about 50 have the machines to measure CD4 T-cell counts), then you can’t start treating all the people who need it. He ends by making a convincing case for, at the very least, giving ART to all pregnant seropositive women in Malawi (and I guess, in the whole of Africa), with a clear recommendation that they continue on medication indefinitely. The objectives of this approach would be to keep mothers alive and healthy while their children
are growing up, and to ensure that the next generation of children are born HIV-free.

And that’s it for the first day.”

Dorian

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Posted in General, General Virology, Vaccines: General, Viruses | 1 Comment »

No hypothetical vaccines please!

14 January, 2011

A new editorial in Elsevier’s Vaccine, by Gregory Poland and JR Hollingworth, gives one much food for thought…especially if one and one’s associates are engaged in vaccinology, however quixotic that quest may be.

Especially quixotic when certain editors take 11 months not to publish one’s HIV vaccine paper, but that’s a story for another day…!

The article is entitled “From Science II to Vaccinology II: A new epistemology“, and is a thoughtful and quite intellectually challenging piece of work.

I have previously indicated that I am not a fan of hypothesis-driven science, however well entrenched it is in the psyches of most who practice it – in fact, I have gone as far as claiming elsewhere (thanks, Alan C!):

“Profound Insight No. 1: hypotheses are the refuge of the linear-thinking.

…I am quite serious in disliking hypothesis-driven science: I think it is a irredeemably reductionist approach, which does not easily allow for Big Picture overviews, and which closes out many promising avenues of investigation or even of thought. And I teach people how to formulate them so they can get grants and publications in later life, but I still think HDS is a tyranny that should be actively subverted wherever possible.”

And here we have two eminent scientists agreeing with me!  Not that they know that they are (or care, I am sure), and nor is it important – for what they have done is write a tight and carefully reasoned justification for moving away from the classical approach in vaccinology, as the complexities of the immune system and responses to pathogens and vaccines render the reductionist approach inadequate to address the problems at hand, and especially those presented by rapidly-mutating viruses.

This really is quite a profound suggestion for change, as the world of vaccinology is notoriously conservative, and it is really difficult to get people even to discuss only mildly paradigm-nudging concepts – oh, like cellular responses possibly being as important for protection against papillomaviruses as sterilising antibody responses? – let alone publish them.

Their final paragraph is especially apposite:

As we move into the world of Vaccinology II, or the “second golden age of vaccinology”, success will come only with the willingness to minimize the current Newtonian framework of thinking, and to adapt a new framework (Science II) that requires novel advanced bioinformatic and chaos theory-like analytic approaches, as well as multi-level systems biology approaches to studying currently unpredictable and uncertain self-organizing complex systems such as host immune response generation. Such work is difficult, expensive, challenging, and absolutely necessary if major advances are to occur in vaccine biology generally, and vaccine immunogenetics specifically.

This is fundamental stuff: I sincerely hope people in the field of HIV vaccines in particular give it some heed, as there the funding paradigm has actually shifted back towards requiring that everything be “hypothesis-driven”  – and I think this is a retrograde step, when the funding agencies (NIH, Gates Foundation) need to take more, rather than fewer risks, if we are to make any meaningful progress in our lifetimes.

While I am also not a fan of “systems biology” – because I think it is a catch-all term for what amounts to multidisciplinary research, and many of its proponents are brash snake-oil salesmen – modern vaccinology  really is a fertile field to plough using the new approaches.  Poland and Hollingworth put it well:

Similarly, as applied to understanding host variations as causative of inter-individual heterogeneity in immune responses  to such viruses, a Newtonian–Descartian view is entirely inadequate….

Rather than general principles, Vaccinology II and the new biology  is increasingly informed by principles such as pattern recognition, systems with non-linear qualities, and complex networks—often  focused at the individual, rather than population, level.

Amen to that.  Now, to get some money to do that…!!  B-)

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Posted in General Virology, HIV, Influenza viruses, Vaccines: General | 4 Comments »

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