Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

January 20th, 2009

Immunodominance: Not so much?

The Nervous System (Fritz Kahn (1888-1968))
The Nervous System (Fritz Kahn (1888-1968))

Is “immunodominance” just what you get when you measure the wrong place?

Usually, when you look at T cell immune responses to a virus, they’re pretty strongly biased. That is, although the T cells are theoretically, and often observably, able to recognize a wide range of target peptides, the immune response is strongly focused on just a handful of these peptides, while the remaining pool of potential targets is either ignored altogether or given a cursory glance by a handful of T cells. This phenomenon is known as “immunodominance“, and it’s seen with  immune responses to all sorts of pathogens. In some cases — such as for HIV — it’s likely that a strongly immunodominant response is harmful, because it makes it easier for the infecting virus to mutate away from immune control. But in the vast majority of cases the immune response, be it never so immunodominant, does a perfectly good job of controlling the virus; which is why we’re able to easily control most of the viruses that we’re exposed to.

Usually when you measure an immunodominant response, you’ll take lymphocytes from the most abundant, easily-accessed place you can find. That would be blood, in humans; in mice you’d probably take a spleen or lymph nodes.  Some viruses like to hang out in these places, and these include some of the more popular research viruses.

But most of the viruses we’re exposed to don’t infect blood or secondary lymphoid organs; they infect the lungs, or the skin, or neurons, or some other tissue. When we measure the blood response, we believe we’re measuring a good approximation of the real response ongoing in the infected tissue, but that’s mostly been an assumption, not a demonstrated fact.

Recently there’s been some work starting to feel out how similar the tissue response is to the blood/lymphoid organ response. For example, I talked here about work establishing the timing of immune responses in the lungs, vs. the blood. In this case, the overall patterns were similar, though the details were somewhat different.

But that was only really looking at a fairly big picture — overall patterns. What about specifics of target recognition? In particular, is the immunodominance we measure in the blood what actually happens on the battlefield?

I’m only aware of a couple of studies that look at this at all, and those were mainly as asides, noticed in passing. Yewdell’s group has shown in a couple of paper that  infecting mice with poxviruses by different routes leads to differences in immunodominance:1

The latter point is underscored by our observation that the ID hierarchy varies with the route of infection, the first observation of its kind to our knowledge. It will be of great interest to determine the underlying mechanism. 2

I’ve been told of unpublished data that show different immunodominant responses between lung and spleen, as well; also with a poxvirus.

But in those few examples, the epitopes were all known ones.  Known epitopes moved up or down a notch or two in the immunodominance hierarchy. A recent paper from Bob Hendricks’ group3 shows that T cells in the tissues can recognize things that are apparently not seen at all in the blood or spleen.

Baines HSV
Electron tomogram of HSV4

Here they used herpes simplex virus (HSV) in C57BL/6 mice, which have long been believed to almost entirely focus their CD8 T cell response on a single peptide. Hendricks’ group has been looking at the immune response to HSV in the brain, where the virus sets up a latent infection  (I’ve talked about some of his findings here and here).  Contrary to more traditional concepts, it’s now becoming clear (from Hendricks’ work, and that of others) that T cells in the brain are important in controlling latent HSV infection.

In this paper, he found that the immune response in the brain is much more diverse, fairly strongly recognizing at least one  peptide other than the known dominant job.  Because the “normal” (that is, non-neuronal) immune response is so focused, this almost certainly means that the active immune response, down at the pointy end where the T cells are actually working, are responding to altogether different peptides.

It’s generally been assumed, as I say, that the easily-accessed blood or secondary lymphoid tissue is a reasonable approximation of what’s going on in the actual sites of action, in the peripheral tissues — in other words, the idea has been that there’s more or less equal flow of cells between the tissues and the blood and lymph. The recent work on timing and kinetics that I mentioned here sort of supported that assumption, but now we have to wonder whether in fact there’s some kind of filter that keeps some sets of T cells from entering, or staying in, the blood.

We also have to wonder if the whole “immunodominance” paradigm is what we think it is. Could immunodominance represent the filter between blood and tissues, rather than the actual formation of responses? I actually don’t think that would explain immunodominance in general (for one thing, we see strong immunodominance for viruses of lymphocytes, where the blood is the site of infection, so there shouldn’t be a filter) but it’s something to factor in.


  1. D. C. Tscharke (2006). Poxvirus CD8+ T-Cell Determinants and Cross-Reactivity in BALB/c Mice Journal of Virology, 80 (13), 6318-6323 DOI: 10.1128/JVI.00427-06
    D. C. Tscharke (2005). Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines Journal of Experimental Medicine, 201 (1), 95-104 DOI: 10.1084/jem.20041912[]
  2. D. C. Tscharke (2005). Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines Journal of Experimental Medicine, 201 (1), 95-104 DOI: 10.1084/jem.20041912[]
  3. B. S. Sheridan, T. L. Cherpes, J. Urban, P. Kalinski, R. L. Hendricks (2008). Reevaluating the CD8 T cell response to HSV-1: Involvement of CD8 T cells reactive to subdominant epitopes Journal of Virology DOI: 10.1128/JVI.01699-08[]
  4. Electron tomogram of a HSV nucelocapsid completing envelopment , from Baines, J. D., C. E. Hsieh, E. Wills, C. Mannella, and M. Marko. 2007. Electron tomography of nascent herpes simplex virus virions. J Virol 81: 2726-2735.[]
January 16th, 2009

Viruses jumping species

CoronavirusOne of the reasons for epidemics and pandemics, is a virus that jumps from one species to a new one.  Among the original population (let’s call it the “natural host”), there’s a certain level of immunity . Individuals have been infected and survived, and walk away with some resistance to the virus.  That limits the virus’s ability to spread among the natural host.  If the virus can jump into a new host species, then none of the population will have ever seen that virus before, and there is the potential to burn through the population in a sudden, explosive pandemic.

Some obvious examples should jump to your mind: HIV jumping from non-human primates into humans; West Nile virus moving into North America. The best-documented example may be canine parvovirus entering the world-wide dog population in 1978, which I talked about here.

A more common scenario is for a virus to dip its toe into the new population, but not to establish a permanent, ongoing infection in that population.  Ebola periodically jumps into the human population from bats (probably) and causes serious problems for a while, but hasn’t moved into the larger human population yet.  SARS virus, ditto. Sin Nombre virus, Avian Influenza (so far!), canine distemper moving into seals and lions — these cause sudden but limited epidemics that burn out and don’t set up a long-term relationship in the new host.

UGA CoronavirusesHow can we tell which route will be followed?  Did SARS in humans fizzle out because it wasn’t well adapted (even though it was visibly evolving to be human-adapted at a furious rate) or did the containment policies that were slapped on travel and so forth catch it before it has time? I have no idea how to generalize, and I don’t think anyone does.

Which means it’s probably a good idea to watch closely for any examples of species jumping, and to monitor it closely.

Right now, there’s apparently an example of a coronavirus (same virus type as causes SARS, by the way) that has moved from pigs into dogs. 1 In fact, these viruses seem to be hydrids — recombinants that are part dog coronavirus, part swine coronavirus.  This is very reminiscent of the major changes in influenzaviruses that happens a couple of times per century, and that is the concern with avian flu.

So far, these new viruses don’t seem to be very virulent, at least on their own; they didn’t cause disease experimentally, though they were isolated from natural cases of sick dogs.  Something like this has apparently happened at least once before, about 10 years ago, with a previous canine/pig coronavirus recombinant,2 and that one didn’t take off in the canine population.

I don’t know if it’s possible to draw general conclusions about new viruses and pandemics, but I am sure it’s worth trying.


  1. N. Decaro, V. Mari, M. Campolo, A. Lorusso, M. Camero, G. Elia, V. Martella, P. Cordioli, L. Enjuanes, C. Buonavoglia (2008). Recombinant Canine Coronaviruses Related to Transmissible Gastroenteritis Virus of Swine Are Circulating in Dogs Journal of Virology, 83 (3), 1532-1537 DOI: 10.1128/JVI.01937-08[]
  2. Wesley, R. D. 1999. The S gene of canine coronavirus, strain UCD-1, is more closely related to the S gene of transmissible gastroenteritis virus than to that of feline infectious peritonitis virus. Virus Res. 61:145-152[]
January 14th, 2009

Why a vaccine failed, and maybe a fix

Jenner vaccinating a child
Jenner vaccinating a child

As I said last week, one of the biggest vaccine fiascos was the vaccine against respiratory syncytial virus (RSV) that was introduced in the 1960s. RSV is essentially a universal infection of children; it usually causes fairly mild respiratory disease, but because it’s so common the small fraction of cases that are more severe, end up being a leading cause of hospitalization for children. The vaccine was supposed to prevent that. As it happened, the vaccine itself didn’t cause any problems on its own; but children vaccinated with this RSV vaccine, who then later on were infected with RSV, actually had worse disease than those children who were uninfected. (Two children died.)

This enhanced respiratory disease (ERD) was really puzzling at the time, because the vaccine actually did induce a good, strong antibody response. But the antibody turned out to be non-protective. Just having an antibody response is not enough; the overall immune response needs to be involved and protective.

(I think we’re seeing some parallels to this concept now with T cell responses, where we are discovering that just having CD8 T cells doesn’t necessarily offer protection against things like HIV and hepatitis C virus, whereas the quality of the CD8 cells — now being measured as the range of cytokines they can produce — seems to be correlated with protection.)

The RSV vaccine turned out to trigger a TH2 type immune response. TH1/TH2 type responses are now a fundamental concept in immunology, but that hypothesis is a relatively new. Tim Mossman proposed it in 19861 and there was a significant lag before it was widely accepted. I think one of the findings that helped make TH1/TH2 accepted was the finding that the RSV vaccine triggered a strong TH2 immune response,2 compared to the actual virus infection which mainly causes TH1-type immunity. This — to me, anyway — abruptly made the paradigm look less like a laboratory curiosity only seen in mice, and more like a real, clinically important phenomenon.

ABCs of RSVSo the TH2 immune response seemed to more or less explain why the RSV vaccine caused disease. TH1 immune responses are generally protective against viruses, while TH2 immune responses are apparently more geared toward parasitic worms; TH2 responses tend to induce eosinophils and allergic-type responses, and that’s consistent with the clinical disease seen in the vaccinated children who got ERD.

But why did the vaccine induce a TH2 response? This is, of course, a huge question, especially if you’re trying to develop a new antiviral vaccine. One suggestion was the the vaccine screwed up the viral antigens too much. The vaccine used a formalin-inactivated virus, and the proposal was that the formalin alters the virus antigens and that directly caused the abnormal response3 If so, then this is a potential problem for any formalin-inactivated vaccine.

A new paper4 reaches a different conclusion. They say that formalin isn’t the main problem; rather, it’s the lack of adjuvant stimulation. Specifically, they say, you need to stimulate innate immunity via toll-like receptors (TLRs). Unless you do this, B cells don’t become completely activated, and though B cells produce antibodies the B cells don’t progress toward affinity maturation. That is, the normal process where antibodies are selected and shuffled to produce ultra-strong binders to their target antigens never gets underway. As a result, the vaccine induces low-affinity antibodies, and these low affinity antibodies are not protective.

It’s not clear — according to this model — whether the TH2 bias is actually the problem. Immune responses become biased to TH2 when there’s little innate immune stimulation, so the low affinity antibody and the TH2 response go hand in hand. Steve Varga (who has a nice commentary5 on this paper) has shown that some of the TH2 effects that were believed to be important in the pathogenesis of the ERD are not necessarily critical after all. Still, Varga and Delgado et al do seem to still feel that the TH2 shift is part of the disease.

The really exciting part of this finding is that it might actually be easy to fix. We now know a lot about TLR stimulation, and it should be possible to include TLR ligands along with the RSV vaccine:

These findings … open the possibility that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation. 4

Will this induce strong, protective immunity? Hopefully we’ll find out soon.


  1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348-2357[]
  2. Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus. Graham BS, Henderson GS, Tang YW, Lu X, Neuzil KM, Colley DG. J Immunol. 1993 Aug 15;151(4):2032-40.[]
  3. A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. Moghaddam A, Olszewska W, Wang B, Tregoning JS, Helson R, Sattentau QJ, Openshaw PJ. Nat Med. 2006 Aug;12(8):905-7.[]
  4. Maria Florencia Delgado, Silvina Coviello, A Clara Monsalvo, Guillermina A Melendi, Johanna Zea Hernandez, Juan P Batalle, Leandro Diaz, Alfonsina Trento, Herng-Yu Chang, Wayne Mitzner, Jeffrey Ravetch, José A Melero, Pablo M Irusta, Fernando P Polack (2008). Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease Nature Medicine, 15 (1), 34-41 DOI: 10.1038/nm.1894[][]
  5. Steven M Varga (2009). Fixing a failed vaccine Nature Medicine, 15 (1), 21-22 DOI: 10.1038/nm0109-21[]
January 8th, 2009

Vaccine successes, vaccine failures

Polio vaccine vialThe STEP HIV vaccine trial has been in the news a lot and it’s usually described as a “failed” trial. (I may even have described it that way myself.) It’s not really a failed trial, though; it’s a failed vaccine. The trial was successful in that exposed the failure of the vaccine, before the vaccine was widely deployed.

Most failed vaccines are caught this way, assuming they even make it to the clinical trial stage. Even in the old days, before the present clinical trial/licensing system,1 most vaccines were highly effective and safe. I’ve shown stats about the truly spectacular effects of measles vaccine in the USA and in other first- and third-world countries, and I’ve shown what happens when anti-vaccine lies make people stop vaccinating (short answer: Children die).

Anti-vaccine loons use all sorts of distortion and outright lies to deny these effects. But that’s not to say that vaccines have been universally perfect. There’s no doubt whatsoever that vaccines have caused harm. All but the very safest vaccines do have a detectable complication rate. Some have a relatively high complication rate — the vaccine against smallpox, vaccinia virus, probably had the highest complication rate of any widely-used vaccine (somewhere around 1/100,000 – 1/300,000 vaccinees had significant complications), though most vaccines are far safer than that. The smallpox case makes the point obvious, though, that it’s a cost/benefit analysis. If vaccination can save a million lives, but costs ten lives, then most people would agree, however reluctantly, that vaccination is a good thing. 2 These vaccines are still successes.

As an illustration, here’s a  chart showing overall effects of vaccination for a dozen or so diseases:3

Impact of vaccines in the 20th century

However, there are several cases of true vaccine failures. They don’t seem to be widely known — outside of immunology circles, of course, where they’re well-known cautionary tales — so it’s worth mentioning them. For one thing, these stories flatly disprove one of the most common vaccine-loon claims. The conspiracy theories claim that even though vaccines cause harm, the harm is ignored. Yet in these cases, when vaccines did cause harm — even in small numbers — the problems were quickly spotted and the vaccine was forced out of use.

The three cases that jump to mind are the contaminated poliovirus vaccines, the RSV vaccine disaster, and the rotavirus vaccine. Of the three, the RSV vaccine was the worst. (A new explanation for this problem has just been published, and I’ll talk about it next post.)

The polio vaccine contamination thing was in the early days of virology, in 1959. To make a long story short, the polio vaccine virus was grown on monkey cells which turned out to have a virus of their own. This is now known as simian virus 40, SV40, and is a well-known virus now, but that was the first time it was identified. As it turned out, and mainly through luck, the SV40 contaminating the polio vaccine didn’t cause much, if any, disease in the recipients4 (though I’ve heard that immune-suppressed people, many years later, did have problems). It was a wake-up call to check much more thoroughly for unexpected passengers.

The rotavirus vaccine is a more recent example. This was mainly a rare-problem case: A small number of children who received the vaccine had serious problems (intussusception), but the incidence was so low (between 1/10,000 and 1/30,000 recipients) that the clinical trials didn’t have enough power to identify it as a problem. When put into widespread use in the general population, the risk was quickly spotted and the vaccine was withdrawn within a year.5 (This is the counter to the loon’s claim that vaccine risks are ignored, by the way.) The newer rotavirus vaccines that were recently introduced don’t have this problem.

Finally, that brings us to RSV, respiratory syncytial virus. This was the worst of the three, and the hardest to understand in terms of how the vaccine ever got licensed. To make this long story short, the RSV vaccine actually made the disease worse! RSV is a very common childhood virus, essentially infecting every child. Most have no problems, though because the disease is so common even rare complications in terms of percentages, turn out to be large in terms of actual numbers. But children previously vaccinated turned out to have much, much more frequent, and much more severe, complications. (Again, this was recognized and the vaccine was withdrawn, though I think it was not as quick as would happen today.) I’ll talk more about the RSV vaccine next time.


  1. And I don’t know anything about the history of this, so if anyone does, please enlighten me[]
  2. Of course, the lives saved are invisible — people who remain healthy — while the lives lost are apparent. That means the equation isn’t as simple as counting saved vs lost and going with the larger number. But it’s an equation, is my point.[]
  3. Diptheria, Measles, Mumps, Pertussis, Polio, Rubella, Smallpox, Tetanus, Hepatitis A, Acute hepatitis B, Invasive Hib, invasive pneumococcal disease, and Varicella; Data are mostly from CDC, but include some other sources[]
  4. Dev Biol Stand. 1998;94:183-90. Discovery of simian virus 40 (SV40) and its relationship to poliomyelitis virus vaccines. Hilleman MR.[]
  5. Curr Opin Gastroenterol. 2005 Jan;21(1):20-5 Rotavirus vaccines and intussusception risk. Bines JE.[]
January 5th, 2009

Twelve months of Mystery Rays

Protect against malaria 1941In 2008, I talked about maybe 100-200 papers here on Mystery Rays. Here are some of my favorite publications of 2008. I’m not saying these are the most important of the year, or anything like that; these are just papers that I thought covered something cool and did so in a nice clean way. As with last year, I managed to narrow it down to 12 subjects, but this time I couldn’t quite cut it down to 12 specific papers this year. Whatever, dude.  In no particular order:

  1. Malaria vaccines. People have been working on effective malaria vaccines for decades, without much to show for it. In 2008, clinical trials with a new vaccine candidate showed encouraging, though not overwhelming, protection. (I talked about malaria eradication here and here.)

    Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. 1
    Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. 2

  2. Mechanism of action of alum adjuvant. Alum has been the by far the most common adjuvant used in human vaccines, but until recently we didn’t know how it works. There were a bunch of papers in 2008 that at last offered explanations for alum’s effect: It acts through a particular branch of the innate immune sensor mechanism. (I talked about alum here and here.)

    Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122-1126. 3
    The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol. 2008 Aug;38(8):2085-9. 4
    Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol. 2008 Jul 1;181(1):17-21. 5

  3. Immune evasion by tumor cells has been shown in a number of cases.  This year, it was shown that natural killer (NK) cells — or at least an NK cell receptor — in important in controlling tumors. (I talked about this paper here.)

    NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. Immunity 28, 571-580. 6

  4. HSV-infected ganglionT cells recognize latently-infected neurons. The most characteristic aspect of herpesviruses is their ability to become latent — to set up a long-term (often lifelong) infection in some cell type, without destroying the infected cells, and without being eliminated by the immune system. Herpes simplex viruses are the archetypal herpesvirus, yet in the past few years it’s become apparent that everything we thought we knew about herpes simplex latency is wrong. Herpes simplex latent infection turns out to be recognized and controlled, but not eliminated by immune T cells. (Here is my post on this paper.)

    Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268-271. 7

  5. … What’s more, the view that HSV sets up a latent infection and then only rarely reactivates also turns out to be wrong. It seems that HSV is constantly reactivating from latent infection, but mainly in very short bursts. If you don’t monitor patients very, very closely — like swabbing them several times a day — you’ll miss most of the reactivations, so that it looks as if reactivation is rare.

    Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J. Infect. Dis. 198, 1141-1149 8

  6. … and even before latent infection, immune control may be critical. There seems to be a very narrow window of opportunity for immune responses to attack a herpes simplex infection before the virus slips up into neurons and establishes the latent infection. (More here.)

    CD8(+) T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunol. Cell Biol. 86, 666-675 9

  7. Immunodeficiency virus immune escape. One of the major barriers to immune control of HIV is the virus’s ability to mutate and escape recognition by the immune system. This has been recognized for a long time, but techniques to measure and analyze this continue to improve. Here’s a representative paper looking in detail at immunodeficiency virus immune escape.

    Vaccination and Timing Influence SIV Immune Escape Viral Dynamics In Vivo. PLoS Pathog 4(1): e12 10

  8. Adenovirus evades NK cells. The first virus that was shown to have a way of blocking recognition by T cells was adenovirus, via its E3gp19k protein. Identified in the 1970s, there were a flurry of articles on the protein, and then it kind of languished, as people assumed the story was mined out. In 2008, though, it was shown that E3gp19k is much more potent that originally believed, because it also blocks recognition by natural killer (NK) cells. Another reminder that viruses are capable of much more subtlety than we give them credit for. (I talked about this here.)

    Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B. J. Virol. 82, 4585-4594 11

  9. A new mechanism of immune evasion. One of the rather puzzling things about viral immune evasion is that even closely-related viruses often seem to have evolved their own, independent, approaches to the problem. Kalus Fruh showed that rhesus cytomegalovirus has a really weird way of blocking T cell recognition, a mechanism that so far seems to be unique to this virus.  In the past, weird virus immune evasion things have led to important advances in normal cell biology; maybe this will, too.

    Signal Peptide-Dependent Inhibition of MHC Class I Heavy Chain Translation by Rhesus Cytomegalovirus. PLoS Pathogens PLoS Pathog 4, e1000150. 12

  10. Cancer vaccination remains tantalizingly close but just out of reach; clinical trials still show occasional spectacular successes coupled with more failures. One of the problems is to identify tumor antigens that are suitable targets for common vaccines. Endogenous retroviruses may, perhaps, be such a target. (More on HERVs and immunity here.)

    Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest 118, 1099-1109 13

  11. T cell activationGenome sequencing has been getting faster and cheaper at an amazing pace. We’re now entering an age when viruses can be tracked through epidemics by whole-genome sequencing, following through mutations and viral evolution throughout the epidemic and using the sequence to predict and analyze the stages of the epidemic. (More here.)

    Transmission pathways of foot-and-mouth disease virus in the United Kingdom in 2007. PLoS Pathog. 4, e1000050 14

  12. Meticulous tracking of T cells demonstrated last year that for CD4 T cells it is possible to count the tiny handful of naïve T cells for any one specificity, hidden though they are in the ocean of other T cells. This year Leo LeFrancois appled the same technique to cytotoxic T lymphocytes (CTL) and proposed that the number of naïve T cells is a major determinant of the entire downstream immune response. (Post is here.)

    Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859-869. 15


  1. Abdulla, S., Oberholzer, R., Juma, O., Kubhoja, S., Machera, F., Membi, C., Omari, S., Urassa, A., Mshinda, H., Jumanne, A., Salim, N., Shomari, M., Aebi, T., Schellenberg, D. M., Carter, T., Villafana, T., Demoitie, M. A., Dubois, M. C., Leach, A., Lievens, M., Vekemans, J., Cohen, J., Ballou, W. R., and Tanner, M. (2008). Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. doi:10.1056/NEJMoa0807773[]
  2. Bejon, P., Lusingu, J., Olotu, A., Leach, A., Lievens, M., Vekemans, J., Mshamu, S., Lang, T., Gould, J., Dubois, M. C., Demoitie, M. A., Stallaert, J. F., Vansadia, P., Carter, T., Njuguna, P., Awuondo, K. O., Malabeja, A., Abdul, O., Gesase, S., Mturi, N., Drakeley, C. J., Savarese, B., Villafana, T., Ballou, W. R., Cohen, J., Riley, E. M., Lemnge, M. M., Marsh, K., and von Seidlein, L. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. doi:10.1056/NEJMoa0807381[]
  3. Eisenbarth, S. C., Colegio, O. R., O’Connor, W., Sutterwala, F. S., and Flavell, R. A. (2008). Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122-1126. doi:10.1038/nature06939
    Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome.
    Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, Bergen IM, Castillo R, Lambrecht BN, Tschopp J.
    J Immunol. 2008 Sep 15;181(6):3755-9.[]
  4. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity.
    Franchi L, Núñez G.
    Eur J Immunol. 2008 Aug;38(8):2085-9. []
  5. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3.
    Li H, Willingham SB, Ting JP, Re F.
    J Immunol. 2008 Jul 1;181(1):17-21. []
  6. Guerra, N., Tan, Y. X., Joncker, N. T., Choy, A., Gallardo, F., Xiong, N., Knoblaugh, S., Cado, D., Greenberg, N. R., and Raulet, D. H. (2008). NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. Immunity 28, 571-580. doi:10.1016/j.immuni.2008.02.016[]
  7. Knickelbein, J. E., Khanna, K. M., Yee, M. B., Baty, C. J., Kinchington, P. R., and Hendricks, R. L. (2008). Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268-271. DOI: 10.1126/science.1164164[]
  8. Mark, K. E., Wald, A., Magaret, A. S., Selke, S., Olin, L., Huang, M. L., and Corey, L. (2008). Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J. Infect. Dis. 198, 1141-1149. DOI: 10.1086/591913[]
  9. Wakim, L. M., Jones, C. M., Gebhardt, T., Preston, C. M., and Carbone, F. R. (2008). CD8(+) T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunol. Cell Biol. 86, 666-675; doi:10.1038/icb.2008.47[]
  10. Loh, L., Petravic, J., Batten, C., Jane, Davenport, M., P., and Kent, S., J. (2008). Vaccination and Timing Influence SIV Immune Escape Viral Dynamics In Vivo. PLoS Pathog 4(1): e12. doi:10.1371/journal.ppat.0040012[]
  11. McSharry, B. P., Burgert, H. G., Owen, D. P., Stanton, R. J., Prod’homme, V., Sester, M., Koebernick, K., Groh, V., Spies, T., Cox, S., Little, A. M., Wang, E. C., Tomasec, P., and Wilkinson, G. W. (2008). Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B. J. Virol. 82, 4585-4594. doi: 10.1128/JVI.02251-07.[]
  12. Powers, C. J., and Fruh, K. (2008). Signal Peptide-Dependent Inhibition of MHC Class I Heavy Chain Translation by Rhesus Cytomegalovirus. PLoS Pathogens PLoS Pathog 4, e1000150. doi:10.1371/journal.ppat.1000150[]
  13. Takahashi, Y., Harashima, N., Kajigaya, S., Yokoyama, H., Cherkasova, E., McCoy, J. P., Hanada, K., Mena, O., Kurlander, R., Abdul, T., Srinivasan, R., Lundqvist, A., Malinzak, E., Geller, N., Lerman, M. I., and Childs, R. W. (2008). Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest 118, 1099-1109. doi:10.1172/JCI34409.[]
  14. Cottam, E. M., Wadsworth, J., Shaw, A. E., Rowlands, R. J., Goatley, L., Maan, S., Maan, N. S., Mertens, P. P., Ebert, K., Li, Y., Ryan, E. D., Juleff, N., Ferris, N. P., Wilesmith, J. W., Haydon, D. T., King, D. P., Paton, D. J., and Knowles, N. J. (2008). Transmission pathways of foot-and-mouth disease virus in the United Kingdom in 2007. PLoS Pathog. 4, e1000050. doi:10.1371/journal.ppat.1000050[]
  15. Obar, J. J., Khanna, K. M., and Lefrancois, L. (2008). Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859-869. doi:10.1016/j.immuni.2008.04.010[]
December 27th, 2008

2008: The year in review

This year, I read some 200-odd scientific papers (or at least skimmed them). I posted 130 articles here on Mystery Rays; of those, just under 100 were full-length paper discussions, so I probably cited, I don’t know, between 150 and 200 papers here (though not all were from 2008, of course). I aim for about 2 posts a week, so I ended up reasonably close, I guess, in spite of slowing down during heavy teaching and grant-writing periods.

(As well as the full-length posts, I included 16 short quotes that struck my fancy. The remaining 16 included a few updates on XPlasMap, and bits and pieces of baseball, pictures of my kids, and other stuff.)

Some scientific high- and low-lights of 2008, in my highly biased opinion:

Highlight: Encouraging, though not overwhelming, new on the malaria vaccine front. 1 Malaria vaccines have been extensively researched for decades, and this seems to be the best candidate so far. Unfortunately, it’s still not a very good vaccine, with efficacy levels that are in the 60% range — far lower than would be acceptable for most diseases. However, even providing limited resistance to malaria will make a huge impact on population health. As well, seeing even that much effectiveness is encouraging to other vaccine development.

Lowlight: I think the spillover from the 2007 failure of the HIV STEP vaccine trial has continued to be disappointing. A clinical trial can “fail” in that it doesn’t offer clinical success, but still give enough research data to move the field forward. I may be wrong, but it seems to me that the papers following up the STEP trial haven’t managed to build on the failed trial very effectively. (Not the fault of the researchers, but apparently the information simply wasn’t in the trial data.) It’s clear that new approaches are needed, but the STEP trial (so far) hasn’t clearly pointed what those new directions might be.

Personal disappointment (and I’m sure this will aggravate lots of people) is the lack of useful mathematical/computer models that are applicable to immunology. I’ve seen a number of attempts to model immune systems, but so far I haven’t been convinced they actually show anything meaningful, let alone useful.

I’m fascinated and intrigued by modeling of bioloigcal processes, and I think there’s a huge potential there, but to date I can’t say I’ve seen much exciting stuff in the field. (I’m very open to having my mind changed; please let me know if there’s something I should look at again.)

Interesting progress: I think the concepts of anti-tumor immunity continue to progress, slowly but surely, and there are glimmers of clinical utility on the horizon. That said, those same glimmers have been on the horizon for about the past ten years, and I’m not certain that they’re getting all that much closer.

More interesting progress: Organ transplanation is finally starting to take some advantage of regulatory T cells, inducing controlled tolerance in a planned, reproducible manner.2 This has been the holy grail of transplanation biology for decades, and to me, at least, it seems to be almost within grasp now.

In a few days I’ll post my list of my favourite papers of 2008.


  1. Abdulla, S., Oberholzer, R., Juma, O., Kubhoja, S., Machera, F., Membi, C., Omari, S., Urassa, A., Mshinda, H., Jumanne, A., Salim, N., Shomari, M., Aebi, T., Schellenberg, D. M., Carter, T., Villafana, T., Demoitie, M. A., Dubois, M. C., Leach, A., Lievens, M., Vekemans, J., Cohen, J., Ballou, W. R., and Tanner, M. (2008). Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. doi:10.1056/NEJMoa0807773

    Bejon, P., Lusingu, J., Olotu, A., Leach, A., Lievens, M., Vekemans, J., Mshamu, S., Lang, T., Gould, J., Dubois, M. C., Demoitie, M. A., Stallaert, J. F., Vansadia, P., Carter, T., Njuguna, P., Awuondo, K. O., Malabeja, A., Abdul, O., Gesase, S., Mturi, N., Drakeley, C. J., Savarese, B., Villafana, T., Ballou, W. R., Cohen, J., Riley, E. M., Lemnge, M. M., Marsh, K., and von Seidlein, L. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. doi:10.1056/NEJMoa0807381[]

  2. Kawai, T. et al., 2008. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression. N Engl J Med, 358(4), p.353-361 []
December 18th, 2008

What’s in a name?

Polarized CD8 T cell responding to a HSV-infected neuron
Polarized CD8 T cell responding to a HSV-infected neuron

Just because something is called a “cytotoxic T lymphocyte” doesn’t mean it’s actually, you know, cytotoxic. And just because something is called a “lytic granule” doesn’t mean it’s actually lytic.

I’ve posted earlier on the range of functions that CD8 T cells — the so-called “cytotoxic T lymphocytes”, or CTL — actually have. CD8 T cells can certainly deliver cytotoxic signals to their target cells; but it’s become increasingly obvious that this isn’t all they can do. For example, it’s recently been shown that in HIV infections, CD8 T cells that show more than one function (“multifunctional” or “polyfunctional” T cells) are correlated with better control of the virus, whereas T cells that only show one or two functions don’t seem to control HIV. (The diagram to the right is from a seminar by Mario Roederer, and it shows the average functions — for example, the ability to secrete cytokines such as interferon, IL-2, MIP1b, and TNF — in long-term non-progressors, who control HIV relatively well, vs. those who progress and don’t control the virus.)

POlyfunctional T cells and HIV progression (Roederer)In fact, Robert Hendricks’ group just showed that T cell functions are even more complex than that, and they did it in the context of a fascinating problem — control of herpes simplex virus latency and reactivation.1

The movie below shows sort of the traditional view of CD8 cell functions. 2 Here we see a CD8 T cell 9in blue) and a target cell (filled with a green dye). At about 10 minutes (the film is speeded up, don’t worry!) the T cell makes tight contact with the target. Within five minutes, the target loses its dye; this is probably because the T cell is punching holes in the target cell’s membrane, so that internal contents can leak out. This is the caused by the T cell protein “perforin”. But T cells are capable of killing their targets in several ways, and we see a second mode of killing kicking in over the next 45 minutes or so. The target cell starts to bubble up, showing dense internal structures; this is probably the target entering a programmed cell death (apoptosis) pathway, and this is caused by a number of T cell proteins, especially “granzyme B”.

So, perforin and granzyme B are both killer proteins. They’re part of the “lytic granules” found in activated CD8 T cells. What Hendricks’ group has found is that perforin and granzyme B can also protect against herpes simplex infections without actually killing the target cell.

Herpes simplex virus first infects the skin or mucous membranes, then rapidly jumps into the neurons that innervate that patch of tissue and track up the axons to the ganglion. For the familiar and ubiquitous herpes simplex type 1, this is usually the trigeminal ganglion. In the neuron bodies of the ganglion, the virus (supposedly! — this is the traditional view) shuts itself down, reducing its protein levels to an undetectable level, and enters a latent state, where the viral genome hangs out but it’s otherwise pretty much a passive blob. Intermittently, the virus can reactivate from latency (especially after local immunity is reduced, for example due to “stress”), and then it tracks back down the axon to the original site of infection, and sheds into the environment once again. For HSV-1 the reactivations are usually seen the common and fairly harmless cold sores.

That traditional view has been changing. For example, we now know that the virus reactivates far more often than was believed;3 the reactivations come in such short bursts that unless you monitor very closely (swabbing 4 times a day, in the study in question) you’ll miss most of them. And they’re not associated with any lesions, usually.

Another change in the traditional view is that, at least for some, and perhaps most or even all of the infected neurons, the virus doesn’t really shut down protein expression to zero. Levels are drastically reduced, but T cells are incredibly sensitive, and it is now clear that T cells do in fact detect HSV-infected neurons in the ganglia. I posted about this research HERE, noting the evidence that infected neurons are often surrounded by HSV-specific T cells.

So if cytotoxic T lymphocytes are constantly detecting target infected neurons, they should be killing the neurons, right? That’s what “cytotoxic” implies. But clearly that’s not the case. Most of you, sitting reading this now (if anyone has in fact made it this far) have lots of “latent” herpes simplex in your trigeminal ganglia — the vast majority of people are infected. And yet your trigeminal ganglia are not slowly disintegrating under the assault of lytic T cells. The virus will still be there when you’re 70 years old, and your ganglia will still be intact (at least, as far as this is concerned; I make no further promises or guarantees).

So what Hendricks’ group has shown is that, yes, CD8 T cells do recognize HSV-infected neurons (this was already known). And the T cells suppress the virus, preventing it from reactivating; this was already known too. What’s new is that they showed that the T cells need perforin and granzyme B to prevent the reactivation, even though the neurons are not killed! They went on to show that granzyme B (which is a protease, that’s how it causes apoptosis) chops up a critical viral protein, blocking the virus from further protein production. So lytic substances can protect without actually lysing — a new function for CD8 T cells.

It’s not clear to me exactly how this works. For one thing, they also showed that a little later in infection there are other factors that suppress the virus (multifunctional!), and suggested that interferon might play this role. Still, it’s a very cool finding, and reminds us that viruses and immunity are both more complex than we know, and put together are complex cubed.

Note that this does not mean that perforin and granzyme B are not cytotoxic proteins! That’s very clearly their major function.4 What Hendricks’ work does show is that cytotoxicity is not their ONLY function.


  1. J. E. Knickelbein, K. M. Khanna, M. B. Yee, C. J. Baty, P. R. Kinchington, R. L. Hendricks (2008). Noncytotoxic Lytic Granule-Mediated CD8+ T Cell Inhibition of HSV-1 Reactivation from Neuronal Latency Science, 322 (5899), 268-271 DOI: 10.1126/science.1164164[]
  2. And I don’t remember where I got this from. Can anyone remind me of the author?[]
  3. Karen E. Mark, Anna Wald, Amalia S. Magaret, Stacy Selke, Laura Olin, Meei?Li Huang, Lawrence Corey (2008). Rapidly Cleared Episodes of Herpes Simplex Virus Reactivation in Immunocompetent Adults The Journal of Infectious Diseases, 198 (8), 1141-1149 DOI: 10.1086/591913[]
  4. for example, see S MIGUELES, C OSBORNE, C ROYCE, A COMPTON, R JOSHI, K WEEKS, J ROOD, A BERKLEY, J SACHA, N COGLIANOSHUTTA (2008). Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control Immunity DOI: 10.1016/j.immuni.2008.10.010 []
December 4th, 2008

Controlled TRegs: The future is (almost) now

TRegs (JCI)Our bodies are crammed with millions of tiny time bombs: lymphocytes that could begin to attack our own bodies, causing lethal autoimmune disease. Traditionally, it was said that these self-reactive lymphocytes were rare, because they were eliminated during their development and were never allowed to reach maturity. But it’s been known for quite a few years now that that’s not entirely true. The vast majority of self-reactive T cells may, indeed, be destroyed in the thymus, but by no means all. (Something like a couple million T cells leave a happy, functioning thymus every day. If central tolerance is 99.999% perfect, then 10 self-reactive T cells will enter the system every single day — and it only takes a couple of T cells to initiate a lethal disease.)

Why don’t we all die as infants of autoimmune attack, if circulating self-reactive T cells are so (relatively) common? As with just about everything in our body, there are redundant systems. For autoimmunity, the next line of defense is the regulatory T cell (TReg).

TRegs were identified as a phenomenon long ago, in the 1960s and 1970s; but the concept abruptly fell out of favor in 1984 (for fascinating and rather embarrassing reasons I talked about here), and it wasn’t until the new millennium that immunologists really returned to the field (first firmly changing the name from “suppressor T cells” to “TRegs” to keep their feet out of the muck), and the field really exploded 5 or 6 years ago.

TRegs have proved more important and powerful than just about anybody would have believed ten years ago. Even very powerful immune responses can be controlled by TRegs; strong TReg responses can actually allow a complete “take” of an organ transplant, for example (I mentioned some examples here).

 TRegs infiltrate tumor
Regulatory t cells infiltrate tumor tissue

As well as transplants, being able to turn on TRegs has potential for lots of other diseases. Autoimmunity, obviously, could be controlled this way; but also, less obviously, it’s possible that some virus diseases might benefit from a TReg response. HIV infection, for example, is exacerbated when T cells are activated, and monkeys with SIV are resistant to disease when their T cells are less reactive (see here and here); could a controlled TReg response reduce the harmful activation associated with HIV? It may seem counterintuitive to try to treat a viral disease by reducing immunity, but there is some precedent. Rodents infected with hantaviruses develop a TReg response and don’t have much disease (see here), while humans react with a more conventional immune response and have severe disease. And recently, it was shown that elite suppressors of HIV may have an exceptionally strong TReg response.1

Conversely, there are lots of instances where we’d like to turn off TRegs, in a controlled way. Tumors are often associated with TRegs, which very likely prevent a cleansing immune response to the tumor (discussed here). And the well-known observation that the elderly often have poor immunity against various pathogens is at least partly because TRegs build up over time.

This is a very fast-moving field, and there are a several recent papers that show exciting advances. One is a huge basic step forward, and I’ll talk about that later. The others2 are technical advances, developing new techniques (that are much less cumbersome and finicky than some of the previous approaches) to generate large numbers of TRegs in a controlled way. The obvious use for this is in transplants:

The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.3

Controlled TRegs have been a holy grail of transplant biology for years, and it’s exciting to see that we may finally be entering an era when TRegs can be produced and used as tools.


  1. Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation.
    Chase AJ, Yang HC, Zhang H, Blankson JN, Siliciano RF
    J Virol 2008 Sep 82(17):8307-15[]
  2. Including, but not limited to:
    W. Tu, Y.-L. Lau, J. Zheng, Y. Liu, P.-L. Chan, H. Mao, K. Dionis, P. Schneider, D. B. Lewis (2008). Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells Blood, 112 (6), 2554-2562 DOI: 10.1182/blood-2008-04-152041

    In Vitro Expanded Human CD4+CD25+ Regulatory T Cells are Potent Suppressors of T-Cell-Mediated Xenogeneic Responses. Wu, Jingjing; Yi, Shounan; Ouyang, Li; Jimenez, Elvira; Simond, Denbigh; Wang, Wei; Wang, Yiping; Hawthorne, Wayne J.; O’Connell, Philip J. Transplantation Volume 85(12), 27 June 2008, pp 1841-1848.

    Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233

    and a review in Piotr Trzonkowski, Magdalena Szary?ska, Jolanta My?liwska, Andrzej My?liwski (2008). Ex vivo expansion of CD4+CD25+ T regulatory cells for immunosuppressive therapy
    Cytometry Part A, 9999A DOI: 10.1002/cyto.a.20659
     []

  3. Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233[]
November 19th, 2008

Electronic notebooks

Cavemen (Life archives)A couple of years ago I published a paper characterizing a mutant cell line. 1  I had been working, on and off, on the cells for around ten years, and they were already present in the lab when I joined it.  To write the paper I needed to know the details of their generation.  I clambered the ladder to the box marked “1992 LAB BOOKS”, pulled out Ethan’s notes for the year, flipped through them for a few minutes, and copied down the procedure — concentration of EMS, duration of treatment, and so on.  

Since 1992 I’ve used electronic data stored on 5¼-inch floppies, 3½-inch floppies (single and double-sided), Bernoulli drives, zip drives, Jazz drives, CDs, DVDs, and USB flash sticks; as well as on computer hard drives from at least four different OSes, and in God knows how many formats.  

The data on at least five of those media are now almost entirely inaccessible to me (if we were desperate, I’m fairly sure we could retrieve them, but it would be a huge chore).  Probably more than half of the different formats are almost unreadable today.  

Meanwhile, the data in those old-fashioned paper notebook are just as usable today as they were in 1992; and they will be equally usable in another sixteen years.   

I’m seeing a lot of discussion online about electronic lab notebooks, but this is an aspect that I don’t think has been emphasized nearly enough.  I know when you plan an experiment, you expect to publish it (in Nature) next week; but that’s not what always happens, is it.  And even if you do publish in a timely manner, who know what’s going to happen in fifteen years?  (I just thawed out some cells, frozen by a colleague in 1985, to analyze their antigen presentation pathways; something he had no interest in at the time.  He still has his lab notebooks describing his characterization, though, including stuff he didn’t publish at the time.)

Searchable experiments
A crude searchable experiments interface

How many of the protocols out there today are going to be functional in 15 years?  How many web sites from 1992 are still readable today?  (Since HTML wasn’t specified until 1993, the answer is “Not many”.)  History suggests that those electronic notebooks of today will be the impenetrable floppy disks of tomorrow. 2

Electronic notebooks do have one gigantic advantage over paper: Search.  I do use electronic notebooks of one kind or another, and the main reason is so I can search for the half-remembered experiment that used brefeldin A, and find out what concentration.  For years I’ve just used a cobbled-together thing I wrote myself, a HTML interface to an SQLite database linked with a Python cgi script (e.g. the screenshot to the right; click for a larger version).  It works nicely for searching, but it’s not as future-proof as I’d like (it depends on Python, which is being updated to a partially incompatible version soon; SQLite, which is likely to be stable for a few years, but I’m not counting on fifteen; and html, which is evolving as well.)  As well, it’s a little irritating to not have real data in there; so in the past year or so I’ve started using a wiki to keep lab notes in as well.  

I’ve actually made multiple false starts at the wiki/notebook thing, and there’s no guarantee that this latest version will stick, but it’s looking more promising than previous runs.  I’m using DokuWiki, which uses flat text (marked up) files for each page. I trust txt to be readable in 10 or 15 years, so even if (when) the rest of the interface is incompatible there should be usable information there.  It’s also easy to back up, and the wiki in general seems friskier and more responsive than some of the other wikis I’ve looked at.  I’m reasonably sure this will work.

But I’m still backing up to a paper lab notebook, because I know that works.


  1. York IA, Grant EP, Dahl AM, Rock KL (2005). A mutant cell with a novel defect in MHC class I quality control. J Immunol 174:6839–6846. []
  2. Note that I haven’t looked in any detail at the electronic notebooks of today, and really have no idea how future-proof they are.  This is just my prejudice.[]
November 13th, 2008

When activation goes bad

HIV budding from a macrophage
HIV budding from a macrophage

The STEP anti-HIV vaccine trial  received a lot of press coverage last year, when the vaccine was pulled for fear that it actually worsened HIV disease. A number of mechanisms were proposed for the exacerbation.  One of those has now received some support.1

The STEP study used adenovirus vectors, expressing HIV proteins, to induce immunity to HIV. Adenoviruses are ubiquitous viruses in most human populations, usually causing fairly mild upper respiratory tract infections (i.e. cold-like symptoms), and most people have been repeatedly exposed to adenoviruses. As part of the adenovirus/HIV vaccine, people developed immunity to the HIV proteins, and also increased their immunity to the adenovirus component. Unfortunately, the preliminary analysis suggested that those vaccinees with high anti-adenovirus immune responses, were actually more susceptible to HIV, not more resistant. Obviously, that was a bad thing.

One suggestion at the time was that having immunity against adenoviruses might lead to increased activation of the immune system. There was already evidence at the time that activated T cells are more susceptible to HIV infection in several ways, and that evidence has been boosted by several studies since. For example, just the other day there was a paper showing that

… circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell proliferation are key factors in AIDS pathogenesis.2

In fact, in monkey species (e.g. sooty mangabeys) that don’t develop disease after SIV infection, you don’t see a lot of immune activation; whereas those species that do develop disease, show significant immune activation:

SIV-infected SMs3 do not manifest the chronic generalized immune activation that characterizes pathogenic SIV and HIV infections, a process that is thought to play a central role in driving CD4+ T cell depletion through bystander activation and loss of uninfected T cells. 4

HIV infecting a macrophage
HIV infecting a macrophage5

So there was theoretical support for the concept that immunity to adenoviruses could lead to immune activation, which in turn could lead to increased HIV replication, causing increased susceptibility to HIV. The paper I mentioned that provides more direct support 1   also spells out a mechanism in a little more detail, looking at antibodies against adenovirus and their effect on activation; as well as noting that at least one other potential problem might be that the anti-adenovirus response could indirectly cause a reduced anti-HIV response (by killing dendritic cells).

This study (and others) actually point to a couple of useful directions. For one thing, although in this case it seems that immune activation was bad, in most cases it’s just the opposite.6  The anti-HIV vaccine is actually a very special case where we might not want an activated immune response, and even there it’s not strictly activation we want to avoid, just off-target activation. (A strong, activated immune response against HIV is probably a good thing,4 because it can shut down the virus.) This adenovirus trick may be a fairly straightforward way of getting immune activation, if it can be harnessed.

Another point is that in this special case, where immune activation may be harmful, maybe blocking activation would be beneficial. It’s a little counterintuitive to try to suppress the immune response when you’re infected with a virus, but it’s probably worth looking at:

These data suggest that therapeutic strategies to reduce immune activation should be explored, in addition to the classic antiretroviral therapies, in preventing progression to AIDS in chronically HIV-infected individuals.2

Added note: The Michael Palm Treatment Action Group blog has commentary on the STEP vaccine trial conclusions published in The Lancet, as well as a previous series of commentaries on the vaccine trial. Highly recommended.


  1. M. Perreau, G. Pantaleo, E. J. Kremer (2008). Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells Journal of Experimental Medicine DOI: 10.1084/jem.20081786[][]
  2. The Journal of Immunology, 2008, 181: 6687-6691.[][]
  3. SMs: Sooty Mangabeys[]
  4. J Immunol. 2008 May 15;180(10):6798-807[][]
  5. Gross, L., 2006. Reconfirming the Traditional Model of HIV Particle Assembly. PLoS Biology, 4(12), p.e445 EP []
  6. Bad.[]
:)