Mystery Rays from Outer Space

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

August 28th, 2009

Influenza – more diverse than you thought

Virons le virus (Institut Merieux Benelux, 1991)
“Virons le virus” (Institut Merieux Benelux, 1991)

One of the important drivers of influenza virus evolution is mixed infection: Infection of the same individual with two different strains of virus, which can then reassort to generate brand-new viral genomes. This presumably what happened, for example, with the recent swine-origin influenza virus (SOIV): some pig was simultaneously infected with North American swine flu and a Eurasian swine flu, the two reassorted so that two of the Eurasian virus’s segments joined with 6 of the North American segments, and the new virus thus produced turned out, just by chance, to be good at infecting humans.

Reassortment, notoriously, can generate rapid large changes in the personality of the virus. Pandemic influenzas have been reassortants, unrecognized by the population’s immune systems. But that’s not the only possible outcome; reassortants between closely-related viruses can lead to small changes, reassortants between two circulating strains would still be recognized by the immune response, and so on. Reassortment per se isn’t inevitably devastating, the big concern is reassortment between widely-differing viruses — human and avians strains being the major issue today.

I’ve tended to think of multiple infection and reassortment as quite a rare phenomenon. Reassorted influenza viruses appear and circulate relatively often, but not, you know, daily;1 and those are the product of millions upon millions of infected individuals. On the other hand, most reassortments are probably either dead on arrival (their different segments are simply not compatible) or at best very unfit (their different segments make them easily outcompeted by the wild flu that’s already well adapted to the individuals in question). That means we don’t know the frequency of reassortants, because most of them would be invisible to us.

I’ve also tended to think, perhaps naively, that multiple infections would be a little unusual, because the timing would have to be fairly precise. Viruses generally rely on a couple of days of relative peace (immunologically speaking) to quickly replicate and bank a virus load that then keeps pace with the increasing immune response. If Virus B tries to infect you a couple of days after Virus A is already present, Virus B is going to run right into the thick of the immune response to Virus A, never have that chance to bank its progeny virus, and you’d expect it to be quickly overwhelmed. So you probably need nearly simultaneous infections to get a real multiple infection.

Chicago influenza poster 1918
“Influenza is prevalent” (Chicago, 1918)

But this is all speculation. A recent paper2 went out and actually looked for evidence of mixed infection in humans.3 They used previously-collected samples, and this is going to greatly underestimate the extent of mixed infection,4 but they did detect evidence of several mixed infections in their collection of over 1000 influenza samples. A plausible number they offer is about 0.5% of their samples — half a dozen individuals — were potentially mixed infections.5

(Later they suggest, as unpublished data, that the number may be as high as 3%. An important caution, that they don’t mention here, is that the 3% number is from influenza database analysis, and we know that these databases are not high quality — see On the accuracy of the influenza databases and the paper referenced therein6 — in fact, about 3% of the samples in the database are contaminated, so I don’t know if the present authors took this into account when interpreting evidence for mixed infections.)

However, sticking with the 0.5% figure — which is still remarkably high, and would represent tens of thousands of cases per year — they were able to look more closely at several of these samples and confirmed that they did, in fact, represent true mixed infections. This is another spinoff of the rapid, high-throughput sequencing that’s now becoming widely available. One patient, from New Zealand, was simultaneously infected with two viruses:

…one closely related to viruses cocirculating in New Zealand during 2004 and a second lineage that clustered with A/H3N2 viruses that became dominant in the following (2005) influenza season in the southern hemisphere 2

Another, in New York, was infected with two different influenza strains that are antigenically distinct — that is, viruses that would require different vaccines for protection. Remember that influenza vaccines are customized, year by year, to match up against the dominant circulating virus of that particular year. This patient would have needed two distinct vaccines to get adequate protection from his two infections.

A third, “even more dramatic” example was another New Yorker who was infected with two viruses that were not merely antigenically different, but that came from two distinct, broad groups — influenza A and influenza B viruses. I don’t think A and B can reassort, or at least the progeny would be very unlikely to be fit, but it illustrates that very mixed infection is quite possible.

It’s important to note that they were looking for mixed infection, not reassortment. Reassortment woud be much less common than mixed infection — you need mixed infectio nfor reassortment, but it’s not inevitable following mixed infection. Still, the background of mixed infection seems to be rather higher than I thought it would be.

In sum, we propose that mixed infection of diverse influenza viruses, a necessary precursor to reassortment, is a common occurrence during seasonal influenza in humans and will in turn accelerate the rate of adaptive evolution in this virus. In addition, intrahost populations of influenza virus will harbor genetic diversity generated by de novo mutation, which we have not assessed in the current study. As a consequence, we urge that intrahost sequencing be more routinely employed to assess the degree of genotypic and phenotypic diversity in populations of acute RNA viruses. With the advent of high-throughput next-generation sequencing platforms, viral variants are being much more explicitly revealed within specimens, and this type of data can be made available on a routine basis.2


  1. Offhand, actually, I don’t know how often reassortants have been identified. I’ll try to find that[]
  2. Ghedin, E., Fitch, A., Boyne, A., Griesemer, S., DePasse, J., Bera, J., Zhang, X., Halpin, R., Smit, M., Jennings, L., St. George, K., Holmes, E., & Spiro, D. (2009). Mixed Infection and the Genesis of Influenza Virus Diversity Journal of Virology, 83 (17), 8832-8841 DOI: 10.1128/JVI.00773-09[][][]
  3. It would probably be more interesting to look for mixed infection in swine, or wild ducks, but it’s only humans that have enough close attention to detect these relatively rare events.[]
  4. Most samples of a mixed infection are simply going to pick up the more abundant of the viruses present[]
  5. This comes with a large helping of caveats; it could over- or under-estimate the frequency. But it’s a reasonable starting point and they did confirm some of them.[]
  6. Krasnitz, M., Levine, A., & Rabadan, R. (2008). Anomalies in the Influenza Virus Genome Database: New Biology or Laboratory Errors? Journal of Virology, 82 (17), 8947-8950 DOI: 10.1128/JVI.00101-08[]
August 24th, 2009

On the origins of hepatitis C virus

Africa map, 1677
“Some years travels into divers parts of Africa and Asia the Great”
R. Everingham for R. Scot, etc.London 1677

Hepatitis C virus (HCV), one of the classic intravenous-spread viruses, was only identified about 20 years ago.  Where and when did it originate, and how did it spread?

A recent paper1 estimates that the common ancestor of the present world-wide HCV strains was in Guinea-Bissau, around 1470.  From there:

… infections moved to the New World via Benin–Ghana, even when they originated from Guinea–Gambia. … It is therefore likely that the slave trade has played a historical role in the global dissemination of HCV genotype 2. A similar role has previously been proposed for the transcontinental transmission of yellow fever virus prior to mass global travel. 1

The pattern of HCV spread matches the flow of the slave trade.

There’s another very interesting historical finding from this epidemiology.  HCV epidemiology is very different in Cameroon vs. Guinea-Bissau.  In Cameroon, HCV exploded in the early to mid-20th century; whereas in Guinea-Bissau, HCV spread in the 20th century was slower.  The authors here suggest that this reflects different styles of health care in the two countries — aggressive treatment vs. limited treatment.  But it’s an indirect consequence of treatment of other diseases, and the effects on HCV were the opposite of what you’d expect:

We suggest that the differential epidemic histories of HCV genotype 2 in the two countries probably result from historical differences in the large-scale administration of intravenous antimicrobial drugs, decades before the risk of transmission of blood-borne viruses was understood. After World War I, medical care in Cameroun Français was provided mostly by military doctors, and public-health interventions aimed to cover the whole population … In contrast, the health system before the mid-1940s in Portuguese Guinea (now Guinea-Bissau) was more directed towards protecting the health of the European colonists and their Guinean employees. …Thus, the 25 year delay in organizing public-health interventions in Portuguese Guinea, combined with a lower incidence of yaws and trypanosomiasis in this drier land, resulted in a much lower proportion of the population receiving intravenous injections than in Cameroun Français, and a reduced opportunity for iatrogenic HCV transmission. 1

In other words, the aggressive treatment of diseases in Cameroon probably dramatically reduced the frequency of many diseases, but because it involved injections with non-sterile needles, the treatment also managed to spread HCV.  The more lackadaisical attitude in Portuguese Guinea may have let other diseases flourish, but accidentally restricted the spread of IV contaminants like HCV as well.


  1. Markov, P., Pepin, J., Frost, E., Deslandes, S., Labbe, A., & Pybus, O. (2009). Phylogeography and molecular epidemiology of hepatitis C virus genotype 2 in Africa Journal of General Virology, 90 (9), 2086-2096 DOI: 10.1099/vir.0.011569-0[][][]
August 21st, 2009

Vertical transmission of tumors

Pregnant woman (Ivory Coast)
Pregnant woman (Ivory Coast, West Africa)

Recently I’ve mentioned a few cases of transmissible tumors — that is, cases where tumors actually spread from their original host, to other individuals. The two most dramatic transmissible tumors are Canine Transmissible Venereal Tumor (CTVT) and Tasmanian Devil Facial Tumor (TDFT), where the original tumor can spread widely throughout the entire species. (See this post, this one, and this one, for more detail.) There’s also at least one case of a tumor that accomplished a single transmission, from the original patient to the surgeon who operated on him. 1

Tumors aren’t supposed to be able to spread in this way, because they’re essentially foreign transplants — they should be rapidly rejected, as if they were, say, a skin graft between two random people. In this post I talked about how CVTV and TDFT might have arisen. (There are also a number of cases of tumors that spread to immuno-suppressed individuals, such as after organ transplants, but those cases are easier to understand from an immunologic viewpoint.)

When checking up on references for the last post, I ran across a set of transmissible tumors I hadn’t known about: Vertically transmitted tumors, in which tumors spread from a pregnant mother to the fetus in utero.2

This also, I’m glad to say, seems to be very rare, as you’d expect. Even though mother and child are partially tissue-matched, and even though pregnancy is a very special situation, immunologically, the parent and her child are not genetically identical, and should reject grafts from each other pretty efficiently. (Transplants from parent to child still require immune suppressive treatment.) The review I ran across lists a total of 14 cases of vertical spread of tumors, from 18663 to 2002.4 Although they do note that:

Given the lag time between birth and diagnosis in several of the infants, cases of maternal–fetal transmission may not be as rare as the literature would suggest, and the number of cases could be higher as the detection of metastatic tumor in the fetus may go undetected in cases of abortion or maternal–fetal demise. 2

Malignancy during pregnancy isn’t all that uncommon (0.1% of pregnancies, it says here), so the handful of cases with actual spread of the tumor to the fetus are “numerically inconsequential”. What was different about these 14 cases? We don’t really know, in general. Almost all of the described cases are earlier than 1965,5 predating the molecular era of medicine. Perhaps some, or many, of the infants were immune compromised, as the authors note:

Fetuses with a congenital immunodeficiency are likely to be at an even higher risk for the engraftment of such tumor cells.6 Other factors that may affect the likelihood of tumor cells entering the fetal circulation include maternal homozygosity for one of the fetal HLA haplotypes,7 metastatic potential of the maternal tumor, and a high maternal blood and/or placental tumor load. 2

The outcome of this transmission was very poor; only 3 of the 14 children survived the disease.

I don’t really have any lesson to draw from these cases. Without an extensive molecular workup that isn’t available for almost all of these cases, I don’t know that we can learn much about tumor transmission. Still, these stories are worth keeping in mind when thinking about mechanisms of tumor transmission.


  1. Gartner HV, Seidl Ch, Luckenbach C, et al. Genetic analysis of a sarcoma accidentally transplanted from patient to a surgeon. N Engl J Med 1996;335:1494–1496.[]
  2. Tolar J, & Neglia JP (2003). Transplacental and other routes of cancer transmission between individuals. Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology, 25 (6), 430-4 PMID: 12794519[][][]
  3. Friedreich N. Beitrage zur pathologie des Krebses. Virchows Arch 1866; 36:465–477.[]
  4. Tolar J, Coad JE, Neglia JP. Transplacental transfer of small cell carcinoma of the lung. N Engl J Med 2002; 346:1501–1502.[]
  5. Not saying the molecular medicine abruptly switched on in 1965, it’s just a convenient cutoff[]
  6. Pollack MS, Kirkpatrick D, Kapoor N, et al. Identification by HLA typing of intrauterine-derived maternal T cells in four patients with severe combined immunodeficiency. N Engl J Med 1982; 307:662–666.[]
  7. Osada S, Horibe K, Oiwa K, et al. A case of infantile acute monocytic leukemia caused by vertical transmission of the mother’s leukemic cells. Cancer 1990; 65:1146–1149.[]
August 18th, 2009

H/SIV: Even worse than we thought

Chimpanzee (from Darwin)
Disappointed chimpanzee” – J.M. Wood (from Darwin,
“The expression of the emotions in man and animals”, 1872)

Untreated HIV has very, very high mortality, but there are a few people who manage to survive for quite a long time without progressing to AIDS. These long-term non-progressors somehow keep their HIV levels quite low, and it was thought they wouldn’t develop the disease.  But:

Low-level viremia is present in the majority of elite controllers and is associated with higher HIV-1–specific antibody responses. Absolute CD4+ T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time.1

So, even among these apparently-resistant people, there’s still a trend (albeit a slow trend) toward immune deficiency.

HIV is essentially simian immunodeficiency virus (SIV) that’s crossed over into humans.  Several non-human primates naturally have SIV circulating among them, and it’s usually said that in the natural hosts SIV in not harmful.  But:

SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild. … SIVcpz-infected chimpanzees in Gombe have a 10–16-fold increased death hazard compared to uninfected chimpanzees … SIVcpz infection is associated with progressive CD4+ T-cell loss and immune system destruction, which are hallmarks of pathogenic HIV-1 infection. … SIVcpz seems to be less pathogenic than HIV-1, but more pathogenic than HIV-2 and SIVsmm.2

So, even among this apparently-resistant species, there’s still a trend toward immune deficiency.


  1. Pereyra, F., Palmer, S., Miura, T., Block, B., Wiegand, A., Rothchild, A., Baker, B., Rosenberg, R., Cutrell, E., Seaman, M., Coffin, J., & Walker, B. (2009). Persistent Low?Level Viremia in HIV?1 Elite Controllers and Relationship to Immunologic Parameters The Journal of Infectious Diseases, 200 (6), 984-990 DOI: 10.1086/605446[]
  2. Keele, B., Jones, J., Terio, K., Estes, J., Rudicell, R., Wilson, M., Li, Y., Learn, G., Beasley, T., Schumacher-Stankey, J., Wroblewski, E., Mosser, A., Raphael, J., Kamenya, S., Lonsdorf, E., Travis, D., Mlengeya, T., Kinsel, M., Else, J., Silvestri, G., Goodall, J., Sharp, P., Shaw, G., Pusey, A., & Hahn, B. (2009). Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz Nature, 460 (7254), 515-519 DOI: 10.1038/nature08200[]
August 14th, 2009

On cancer mortality

[Cancer] mortality has been systematically decreasing among younger individuals for many decades. … the cancer mortality rates for 30 to 59 year olds born between 1945 and 1954 was 29% lower than for people of the same age born three decades earlier.  … substantial changes in cancer mortality risk across the life span have been developing over the past half century in the United States. … this analysis suggests that efforts in prevention, early detection, and/or treatment have significantly affected our society’s experience of cancer risk.1

Cancer mortality by birth cohort

All-site cancer rates in successive birth cohorts by age of death.
Mortality rates for decadal birth cohorts between 1925 and 2004 are plotted by age at death.
1

But:

The mortality decline we describe in this paper cannot therefore be attributed to an overall decline in cancer incidence. Rather, the net improvement in cancer mortality in birth cohorts born since 1925 seems to reflect a succession of public health and medical care efforts. 1

They point to reduction in smoking, effective treatment of childhood leukemias and lymphomas and testicular cancers of young adulthood, and “increasingly successful screening programs for breast, prostate, and colon cancer” as important factors, and add “We are optimistic that ongoing efforts in very early cancer prevention (such as use of HB and human papillomavirus vaccines), as well as ongoing clinical trials of targeted therapies, will preserve the downward trend of cancer mortality“.


  1. Kort, E., Paneth, N., & Vande Woude, G. (2009). The Decline in U.S. Cancer Mortality in People Born since 1925 Cancer Research, 69 (16), 6500-6505 DOI: 10.1158/0008-5472.CAN-09-0357[][][]
August 13th, 2009

Why aren’t most tumors transmissible?

Canine Venereal Tumor phylogeny
Canine Venereal Tumor phylogeny

Bayman commented, after reading this post:

So isn’t the real question why can’t all tumors be transmissible? If you believe the tumor immunologists, all tumors should be capable of avoiding T cell attack…no??

I don’t have answers, but I can speculate a little. 1

Very quick background: In general, tumors are unique. They arise independently each time, and when their host dies, the tumor dies too. That’s in contrast to pathogens, whic may or may not kill their hosts, but which survive and are transmitted to a new host; pathogen infections are not unique, they have a long evolutionary history reaching back through many individual hosts. Tumors can’t do this, for the same reason that skin grafts are rejected by unrelated animals — tumors are essentially unrelated grafts, and should be very rapidly rejected by the new host.

But in very rare circumstances — there are two known instances, and a couple of other possible ones — tumors have arisen that can be transmitted from one host to another.  The two cases are canine transmissible venereal tumor, and Tasmanian Devil facial tumor.  There have been suggestions that these tumors are unique in some immunological way, but I am not convinced by those arguments: See this post and this one for more background.  That’s not to say that these tumors have no ways of evading the immune system; what I am saying, is that virtually all tumors have some way of evading the immune system, and the functions that have been convincingly described for the transmissible tumors don’t seem all that exceptional for tumors in general.

So, if these tumors can be transmitted, and they aren’t all that extraordinary immunologically, what does make them extraordinary?  As I say, I don’t know, but based on tumor immunology as I understand it, I can make some guesses.

The most important factor, I suspect, has nothing to do with immunology.  These tumors are unusual in that they have a built-in way of contacting new hosts. TDFT is spread through bites, CTVT is spread sexually.  There’s no similar way that, say, a liver tumor, or a brain tumor, could be spread.  So that immediately rules out the vast majority of tumors; even if they could survive after transmission, there’s no chance of a transmission chain. 2  But still, most tumors would be rejected even if they did manage to be transmitted.

The Three E's of tumor immunity
The Three E’s of tumor immunity

What seems to happen with most tumors3 is that proto-tumors appear quite early, but are controlled by the immune system – perhaps for years — and never become detectable.  Many such proto-tumors are completely eliminated by the immune system, and we have no way of telling that they even existed.  Many more are controlled at the half-dozen cell stage, much too small to detect; they aren’t eliminated by the immune system, but they can’t escape and grow either.  A very small percentage of these equilibrium tumors, though, eventually find a way of at least partially escaping from immune control, and begin to grow. (Perhaps the immune system kills 99% of the new cells, but a 1.01% growth rate compounds itself fast enough to be eventually detectable.)  This is the “Three E’s” theory of tumor growth (discussed more here and here) — “Elimination, Equilibrium, Escape”.

Regulatory T cells
Regulatory T cells and cancer

The Three E’s apply to the very small proto-tumors. But there is probably another factor that kicks in once the tumor becomes larger.  Tumors are themselves immunosuppressive — they shut down immunity throughout the entire body, to some extent, but they shut down immunity to themselves very powerfully.  The immune system has powerful safeguards that prevent it from attacking its own body; broadly speaking, tumors are their own body, and in many cases tumors probably also have been selected to massively amplify the normal protective signals. 4 (See this post, and this one, for more on that.)

So here5 is my speculation.  We suspect that the ability to be transmitted is present in several tumors, but they never get the opportunity to transmit.  Of those rarities that do get transmitted, most are rapidly rejected, as foreign grafts.  But a tiny minority of this minority may be able to survive because they have powerful immune suppression abilities on top of their common immune evasion abilities.

Tasmanian Devil crossing
Why did the Tasmanian Devil cross the road?

Were CTVT and TDFT just lucky — just happened to have the right immune suppressive abilities?  I don’t think so.  I think they were in the right place at the right time.  They were tumors that had a mechanism for transmission, and that had some ability to immune suppress, but they would normally have been rejected as foreign grafts.  Except that both of these tumors, I think, arose at a time and place where their population was highly inbred.  CTVT arose, we speculate, as dogs were becoming domesticated; probably a small, inbred, closely-related population.  Tasmanian Devils in general may not be closely related, but I suspect there are sub-populations6 that were closely related and that would not have rapidly rejected skin grafts.  The early version of the respective tumors would not have been rapidly rejected by these closely-related new hosts, giving them a chance to establish their own immune suppressive regime.

Now we have the chance for natural selection of the tumors.  Variants with more powerful immune suppression could spread to a wider range of hosts; variants with standard immune suppression died out with their victims.  In dogs, this natural selection could occur over time; as dogs became gradually more variable, there would be continuous new selection for new tumors that could keep up with the dogs. 7 With the Devils, the selection would be over space: The tumors would be selected for their ability to spread within new sub-populations of the Devils, perhaps through gradually more distantly-related subgroups. Eventually, we see the tumors as being capable of transmission and growth throughout the entire population, but the original tumor might not have had this ability.

Channel Island Fox
Rapid MHC diversity in Channel Island Foxes

This model suggests that humans are probably not at great risk of having a transmissible tumor spread in us; and the same is true for most species.  You need the combination of an inbred sub-population with a mechanism of tumor spread and the right kind of tumor. And inbred populations are usually a transient thing; MHC becomes diverse very rapidly, and then the window for tumor establishment is closed.

But this is just a guess, so don’t be too comforted.


  1. And by the way, I disagree with Bayman’s suggestion here (“Tumor Immunology Is A Waste of Time”) that he “find[s] it impossible to believe that effective therapy will ever achieved by artificially stimulating the immune system to attack weak and largely self antigens.” But this post is already too long, so I’ll save my answer for another time.[]
  2. There’s at least one case of a surgeon who apparently contracted a patient’s tumor after cutting himself during surgery — given the option, perhaps many more tumors could be transmissible, but don’t get the chance.[]
  3. Not necessarily those induced artificially, with high doses of carcinogens or with powerful oncogenes, but with those that arise naturally, in older individuals[]
  4. I suspect that tumors have many ways of achieving this localized immune suppression.  I also suspect that different tumors have different dependence on this localized immune suppression.  Those tumors that were highly successful as proto-tumors might already be very good at avoiding immunity — for example, they may secrete tons of TGF?, or otherwise have very powerful TReg-inducing abilities — and only need to shut down a little.  Those that barely squeaked by as proto-tumors, may have very potent immune suppression.  I don’t think the mechanisms for this tumor-based immune suppression are very well understood, though over the next couple years they probably will be. []
  5. Finally![]
  6. Subpopulations that are now, probably, extinct, because of the tumors[]
  7. I’m told that CTVT is eliminated faster or slower in different dogs.  It would be very interesting to correlate this with MHC types, to see if there’s still some effect of rejection even after 50,000 years of selection on these tumors.[]
August 11th, 2009

Adaptive immunity

This is your monkeypox infection
with an adaptive immune response:
This is your monkeypox infection
without an adaptive immune response:
Monkeypox in WT mice Monkeypox in SCID mice

Any questions?

(From
Osorio, J., Iams, K., Meteyer, C., & Rocke, T. (2009). Comparison of Monkeypox Viruses Pathogenesis in Mice by In Vivo Imaging PLoS ONE, 4 (8) DOI: 10.1371/journal.pone.0006592
Wild-type (immune-competent) mice (left) or SCID mice (no B or T cell response) were infected with monkeypox virus expressing luciferase. Mice on the left were uninfected controls.  The colors show the presence of monkeypox virus in the mice, with intensity (redder) representing more virus.  The SCID mice died on day 9, while the normal mice cleared the infection.)

August 7th, 2009

Antibodies are OK, really

Broadly neutralizing anti-HIV antibody
Broadly neutralizing anti-HIV antibody
in contact with HIV gp120

My research is focused on T cell responses to viruses, so I don’t tend to talk about antibodies all that much here. For that matter, I personally don’t find antibodies very interesting, research-wise. But I don’t want to dis antibodies as clinical entities, and a few recent papers emphasize how useful they can be. (See also my previous post, Antibody-based vaccines)

Very brief background: Antibodies (also known as immunoglobulins) and T cells are the two branches of the adaptive immune response. The adaptive immune response, invented by sharks1 is capable of a broad, flexible, and long-lasting response to pathogens, contrasting to the relatively narrow and inflexible innate immune response. The T cell response involves cells as the effectors; the antibody response involves (surprise!) antibodies, which are simple proteins, usually soluble — that is, floating freely around in the blood or in various bodily secretions. Antibodies can neutralize pathogens in various ways, almost all of which require the antibody to physically bind to the pathogen. That means that the target on the pathogen has to be exposed (on the outside of the pathogen) where the antibody can see it. It also requires the target on the pathogen to be moderately constant; if antibodies target a particular molecule on a pathogen, and that molecule changes later on, then the pathogen is potentially invisible to the antibody.

Almost all vaccines work mainly through antibodies. Antibodies are relatively easy to induce in a relatively predictable way, whereas even today it’s harder to consistently and reliably induce a protective T cell response to a pathogen. Dead pathogens can induce antibodies, but not T cells (without a lot of jiggering); even pieces of pathogens — subunit vaccines — can induce strong antibody responses; so you can have a big safety factor built in to antibody-based vaccines.

So if antibodies worked for polio and measles and pertussis and so many other highly-effective vaccines, why is there any interest at all in T-cell based vaccines? Simply put, it’s because we’ve already nailed the easy targets for vaccines, and the ones that are left are hard because in general antibody-based vaccines haven’t worked well against them. The 800-pound gorillas out there are malaria and HIV, and antibody-based vaccines against malaria and HIV (and a universal influenza vaccine, the other 800-pound gorilla) simply haven’t been effective. The conclusion has been that effective vaccines against these guys will require T cells.

Anti-lysozyme antibody contacting lysozyme
Anti-lysozyme antibody contacting lysozyme

But that’s not necessarily so. Some papers I’ve run across recently demonstrate that antibodies are more versatile and effective than I usually give them credit for. First, there the observation2 that antibodies actually can protect against HIV. The key seems to be driving constant production of the antibody — in one case,3 via gene therapy rather than conventional immunization. This points to a solution to one of the major problems facing anti-HIV antibodies, but not the second: the constant mutation and variation of HIV surface proteins means that antibodies are usually limited to targeting a very limited number of HIV strains — there’s little cross-protection between strains, in other words. But there’s also some encouraging work on that front, with the identification of broadly cross-reactively neutralizing antibodies. 4 I’ve had questions about how you’d make use of such an antibody — constructing a vaccine that could reliably drive production of this precise antibody would be difficult — but the gene therapy approach would circumvent that problem altogether, so it might kill two birds with one stone.

Malaria vaccines have been under development for decades and none have worked very well. The ones in clinical trials (I’ve talked about them here and here) offer maybe 50% protection — a hell of a lot better than nothing, but as vaccines go pretty awful. A complementary approach to preventing disease in malaria-exposed people — the aim of these sorts of vaccines — would be to reduce spread of the parasite from one infected person to another individual; if this worked, then the disease frequency would, hopefully, drop. 5 I was impressed to see a paper6 describing an antibody-based approach to blocking malaria transmission. The key here seems to be a fairly simple approach (simple in concept, not in practice) of optimizing production of the vaccine target.

As we all know, influenza vaccines have to be tweaked every year, because the vaccines only protect against the very specific strains within the vaccine itself.  (See also this post and this one.)  The problem is similar to HIV — influenza virus surface proteins are highly variable, and antibodies against one strain don’t cross-react against different strains. There’s a lot of interest in develop T-cell-based vaccines with a broader cross-reactivity, but in the meantime there’s some evidence that it might be possible to do something similar using antibodies. There are several papers showing broadly cross-reactive antibodies — for example:

Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. 7

Again, there are technical difficulties — how to drive an immune response against such a precise target, given that it doesn’t arise with any significant frequency in natural infections or with conventional vaccines — but just knowing that the potential is there, is intriguing.

Does this mean we should abandon T-cell approaches and return to tried-and-true antibodies?  I don’t think so; most likely the most effective immunity will be a combination of antibodies and T cells, as happens in natural infections, and in each of these cases the work is extremely preliminary.  But on the other hand, we shouldn’t lose track of the antibodies (boring though they are) in the rush to T cells.


  1. And, in quite a different form, by lampreys and hagfish[]
  2. Reviewed in Haigwood, N., & Hirsch, V. (2009). Blocking and tackling HIV Nature Medicine, 15 (8), 841-842 DOI: 10.1038/nm0809-841[]
  3. Johnson, P., Schnepp, B., Zhang, J., Connell, M., Greene, S., Yuste, E., Desrosiers, R., & Reed Clark, K. (2009). Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys Nature Medicine, 15 (8), 901-906 DOI: 10.1038/nm.1967[]
  4. For example, see this paper and references therein: JULIEN, J., BRYSON, S., NIEVA, J., & PAI, E. (2008). Structural Details of HIV-1 Recognition by the Broadly Neutralizing Monoclonal Antibody 2F5: Epitope Conformation, Antigen-Recognition Loop Mobility, and Anion-Binding Site Journal of Molecular Biology, 384 (2), 377-392 DOI: 10.1016/j.jmb.2008.09.024 []
  5. I think this has been modeled in a paper I saw a while ago, but I don’t remember the details of the model.[]
  6. Chowdhury, D., Angov, E., Kariuki, T., & Kumar, N. (2009). A Potent Malaria Transmission Blocking Vaccine Based on Codon Harmonized Full Length Pfs48/45 Expressed in Escherichia coli PLoS ONE, 4 (7) DOI: 10.1371/journal.pone.0006352[]
  7. Throsby, M., van den Brink, E., Jongeneelen, M., Poon, L., Alard, P., Cornelissen, L., Bakker, A., Cox, F., van Deventer, E., Guan, Y., Cinatl, J., Meulen, J., Lasters, I., Carsetti, R., Peiris, M., de Kruif, J., & Goudsmit, J. (2008). Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells PLoS ONE, 3 (12) DOI: 10.1371/journal.pone.0003942[]
August 6th, 2009

On stupidity and virologists

I’ve quoted this before, but without attribution, because I didn’t know who originally said it:

”The stupidest virus is smarter than the smartest virologist.”

Apparently it was George Klein.

August 5th, 2009

How many human cancers are caused by viruses?

Merkel cell carcinomaWe know that viruses cause a significant minority of human cancers, but we don’t know quite how many, or which, cancers are viral. It’s not as easy as you might think to tell.

The link between viruses and cancer was one of the major breakthroughs in cancer biology, but you could also make a case that that link set cancer research back several years. (Cancer viruses were shown, in chickens, in 19111, but it wasn’t until the 1960s that interest in the concept took off, with Epstein’s demonstration of Epstein-Barr virus (EBV)2 in some human tumors. ) Studying viral oncogenesis has led to huge advances in our understanding of the fundamental biology of cancers. The problem was that there was a general assumption, in the 1960s and 1970s, that viruses were directly responsible for the vast majority of human tumors. If so, all we needed to do was to identify the viruses, develop vaccines against them, and voila! No more cancer!

Of course, it wasn’t that easy. For all the fundamental advances from this concept, it’s been relatively unproductive as far as the bedside is concerned. Most human tumors are not caused by viruses,3 and even those that are, have been really resistant to treatment via direct anti-viral approaches.4 The research units that were established in the 1970s to look at the virus/tumor connection have mostly either disbanded, or taken a different direction now.

Mouse polyomavirus
Mouse polyomavirus

In spite of that, there’s still new and exciting stuff coming out. Most recently,5 Yuan Chang and Patrick Moore identified a new cancer-causing virus of humans. (This was their second breakthrough virus; in 19946 they also found the second-most recent cancer-causing virus of humans, Kaposi’s Sarcoma Herpesvirus.)) This brings to six the number of clearly-linked human cancer viruses: papillomaviruses, HTLV-1, hepatitis B virus, EBV, Kaposi’s Sarcoma Herpesvirus, and the new one, Merkel cell polyomavirus.

I keep meaning to talk about the discovery of Merkel cell polyomavirus, but I’ll set that aside for now. Very briefly, last fall Chang and Moore showed that the presence of the virus is linked to a fairly rare tumor, Merkel cell carcinoma, and they and others have now confirmed the epidemiological association and demonstrated a mechanism for causing tumors. We’re at the stage now of trying to understand the normal biology of the virus. As with most (and all human) cancer viruses, the virus is much more widespread than the tumor. How widespread it is? How does it spread? Does it cause other disease — in particular, is it involved in other tumors?

That last is a particularly interesting question, because although Merkel cell tumors are rare, there are a number of common tumors that could, conceivably, also be caused by the virus; and if the virus causes even a subset of those, then it could be a common cause of cancer rather than an unusual one. So far, though, I think the evidence suggests that the virus is fairly limited in the damage it causes; quite a few groups have looked for the virus in other types of cancer, and although it may be occasionally found7, that most likely reflects general background infection with the virus rather than a causative role.

One exception is a recent paper8 which suggested that the virus might be associated with a subset of squamous cell carcinomas. SCC are a pretty common form of skin tumor, so if MCPyV is a cause of even a subset of SCC it might be a significant cause of cancer.

The problem is that the other studies on MCPyV have shown that it’s out there even in normal, non-diseased humans9 — as you’d expect; the virus must be able to spread and circulate within the human population somehow, and the version of the virus found in Merkel cell tumors is damaged and likely can’t spread, so there must be virus replicating in normal tissues. In this paper, the authors find the virus in a subset of SCC cancers, but I would like to know how many they’d find in normal human skin using the same techniques –  the 15% of positive tumor samples may or may not be significantly different. On the other hand, the SCC-associated virus did show a similar molecular signature to that found in Merkel cell cancer,10 suggesting a causative role. Right now, I’m not completely convinced, but am definitely intrigued.

One really interesting point to add is that — if MCPyV really does cause a significant number of tumors — then it’s been missed all these years, despite high interest in searching for human cancer viruses, until new techniques were applied to the right samples in the right way. Are there other human cancer viruses out there, waiting for the right technique? Is it still possible that most human cancers are caused by viruses? I think that’s pretty unlikely, but the door is still open a crack.


  1. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. Rous, P. 1911. J. Exp. Med. 13:397–411.[]
  2. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. MA Epstein, BG Achong and YM Barr. Lancet 1 (1964), pp. 702–703.[]
  3. The usual educated guess is 20%[]
  4. One major exception, of course, being papilloma virus vaccines, which are a direct outcome of this line of research. But it’s taken a long time to come to fruition. You could also point to vaccination against hepatitis B virus, and a number of veterinary vaccines, as clinical advances arising from the virus/cancer research. But I think it’s fair to say that the energy put into this has been fundamentally, but not clinically, well spent.[]
  5. Feng, H., Shuda, M., Chang, Y., & Moore, P. (2008). Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma Science, 319 (5866), 1096-1100 DOI: 10.1126/science.1152586[]
  6. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma.
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS.
    Science. 1994 Dec 16;266(5192):1865-9.[]
  7. For example, Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors.
    Shuda M, Arora R, Kwun HJ, Feng H, Sarid R, Fernández-Figueras MT, Tolstov Y, Gjoerup O, Mansukhani MM, Swerdlow SH, Chaudhary PM, Kirkwood JM, Nalesnik MA, Kant JA, Weiss LM, Moore PS, Chang Y.
    Int J Cancer. 2009 Sep 15;125(6):1243-9[]
  8. Dworkin, A., Tseng, S., Allain, D., Iwenofu, O., Peters, S., & Toland, A. (2009). Merkel Cell Polyomavirus in Cutaneous Squamous Cell Carcinoma of Immunocompetent Individuals Journal of Investigative Dermatology DOI: 10.1038/jid.2009.183[]
  9. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays.
    Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, Chang Y, Buck CB, Moore PS.
    Int J Cancer. 2009 Sep 15;125(6):1250-6[]
  10. Shuda, M., Feng, H., Kwun, H., Rosen, S., Gjoerup, O., Moore, P., & Chang, Y. (2008). T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus Proceedings of the National Academy of Sciences, 105 (42), 16272-16277 DOI: 10.1073/pnas.0806526105 []
|