Mystery Rays from Outer Space

I’ve been going to some influenza-related conferences in the past week, including the International Conference on Emerging Infectious Diseases in Atlanta.  One of the topics that’s come up several times is the public awareness of the 2009 pandemic H1N1 — there’s a general sense that the general public has lost interest in, or even is actively contemptuous of, the influenza pandemic.  This is causing a lot of frustration, and some bafflement, among the fairly specialized audience here.

I don’t have any particular insights into this, but it’s striking to me that there may be some parallel to the vastly worse 1918 pandemic.  Like 2009, the 1918 flu did virtually all its damage in the USA in less than a month, around October of 1918. (The difference, of course, was that in 1918 the virus killed far more of the people it infected.) In spite of the huge number of deaths that virus caused, though, it seemed to quickly recede into people’s memory as well.  I refer you to Alfred Crosby’s history of the outbreak (Amazon link), which is actually called “America’s Forgotten Pandemic: The Influenza of 1918″, for  a much more detailed discussion.

Is there something about these sort of explosive, but short-lived, outbreaks that lets them be easily replaced in peoples’ anxiety closet?

Short comments about what I’ve been reading (besides several hundred influenza articles):

Hedskog, C., Mild, M., Jernberg, J., Sherwood, E., Bratt, G., Leitner, T., Lundeberg, J., Andersson, B., & Albert, J. (2010). Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011345

The whole deep sequencing thing is going to profoundly change our knowledge of viral pathogenesis, as well as their ecology.

With highly mutation-prone viruses like HIV, hepatitis C virus, or influenza, our understanding of genome sequences has been based on the overall average genome — the average of a vast and diverse population. That average, that we’ve been calling the genome of these viruses, may not even exist as such, and certainly the minor variants that have been missed by traditional methods are also critically important, because they can explode out within a few days to take over the entire population, given the right set of circumstances. For example, if among those minor variants there are a few drug-resistant strains, then as soon as you treat the host, those variants may be able to take over.

In this paper, deep sequencing of people with HIV shows that drug-resistant variants do exist even before treatment, but they are normally very rare. They can take over during treatment with the particular drug, but when treatment is stopped they rapidly regress to rarity. This is presumably because the drug resistance makes the virus globally less fit (in the natural selection meaning of the term). When their more-fit brethren are destroyed by a drug these crippled, but drug-resistant, variants can grow out, but remove that selective pressure and the more wild-type versions take over once again.

As well as implications for treatment, this tells us something about viral reserves:

In most patients, drug resistant variants were replaced by wild-type variants identical to those present before treatment, suggesting rebound from latent reservoirs. ¹

1. Hedskog, C., Mild, M., Jernberg, J., Sherwood, E., Bratt, G., Leitner, T., Lundeberg, J., Andersson, B., & Albert, J. (2010). Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011345[↩]

TcR interacting with artificial membrane1

Why does autoimmune disease (sometimes) follow viral infection?²

It’s a pretty well-known phenomenon, but a definite answer isn’t yet known — and of course there may not be a single answer, there may be multiple causes. We know that many autoimmune diseases seem to be triggered by some sort of infection or inflammation. A classic example is Guillan-Barre syndrome, which is a little more common (though still very rare) in people who have received certain influenza vaccines, but there are plenty of other examples.³ It’s not believed that the infection actually “causes” the disease, but rather that someone who already has a genetic predisposition to the autoimmune disease needs to have some kind of environmental trigger to have the disease actually kick in; and, very rarely, a viral or other infection will provide that trigger.

(The genetic predisposition is clear because, among other points, identical twins are much more likely to both get autoimmune disease than are fraternal twins; whereas the need for an environmental trigger is clear because even if your identical twin gets an autoimmune disease, you’re usually less than 50% likely to get it yourself. Note that I’m lumping together hundreds of different diseases into the “autoimmune” package, and the specific odds and so on differ for each one.)

OK, so if you have a genetic predisposition to autoimmunity — and let’s get more specific, the paper I’m looking at deals with multiple sclerosis (MS) — there’s a small chance that a viral infection will trigger that disease. One of the most popular models for this is “molecular mimicry”. Simplified: This is the notion that a viral protein looks, to a T cell, a little bit like a self protein. The viral protein appears in the context of infection, with its concomitant inflammation and tissue damage and so on, and the T cell is activated to it. The T cell wouldn’t be activated by the self protein because it hasn’t been seen in the context of inflammation before, but once over the activation hurdle the T cell is now able to attack the self protein, and this is autoimmunity.

T cell receptor (top) interacting with MHC

Molecular mimicry is an attractive model, but there’s not a lot of direct evidence for it.  Another possibility has been proposed for a while: Dual TcRs. Normally, T cells can only recognize a single target. This is by “design”;⁴ if the T cell can see two targets, it could get activated by one, and then attack the other, even if the second target was never present during inflammation. This sort of dual target recognition is obviously dangerous, and there are safeguards that mostly prevent it; but some T cells do sneak through with at least the theoretical potential for dual recognition. So what could happen here is that one TcR could be directed against the pathogen, and activate the T cell; then the other TcR, recognizing self, could run amok because it’s now on an activated T cell.

T cells with dual specificity do exist, at a fairly significant frequency (1-8%; at least one source claims as high as 33%, which seems much too high to me), but whether they actually do anything in autoimmunity is up in the air. This idea has been around for a while, but I don’t think there’s been much evidence for it happening naturally. In at least one case, where it was tested in an artificial system, dual TcRs did not seem to be responsible for an automimmune disease. ⁵

The most recent paper offers evidence that (in quite an artificial system) dual-specificity T cells are responsible for multiple sclerosis: ⁶

Our results demonstrate the importance of dual TCR–expressing T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected people, as suggested by the etiology of multiple sclerosis.

It’s an interesting and solid paper as far as it goes, but we’re left with the issue of this being a highly artificial system — mice with manipulated TcRs and manipulated autoimmune disease. Is this a real issue in natural autoimmunity and natural infections? This paper doesn’t really address that, but it does support the notion that it’s something to look more closely at.  (And again, different autoimmune diseases, or even different people with the same disease, may have altogether different triggers.  Maybe some people have molecular mimicry as the trigger while others have dual TcRs and other have who knows what.)

1. By Raghuveer Parthasarath, then in the Groves lab[↩]
2. Also, why are so many of my keyboard keys sticking together? An altogether easier question quickly answered by pointing to my kids “helping” me with my work while holding popsicles[↩]
3. For a review:
   Fujinami, R. (2001). Can Virus Infections Trigger Autoimmune Disease? Journal of Autoimmunity, 16 (3), 229-234 DOI: 10.1006/jaut.2000.0484[↩]
4. I.e. evolution.[↩]
5. McGargill MA, Mayerova D, Stefanski HE, Koehn B, Parke EA, Jameson SC, Panoskaltsis-Mortari A, & Hogquist KA (2002). A spontaneous CD8 T cell-dependent autoimmune disease to an antigen expressed under the human keratin 14 promoter. Journal of immunology (Baltimore, Md. : 1950), 169 (4), 2141-7 PMID: 12165543 [↩]
6. Ji, Q., Perchellet, A., & Goverman, J. (2010). Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs Nature Immunology, 11 (7), 628-634 DOI: 10.1038/ni.1888[↩]

Dendritic cells in the skin (Langerhans cells) form a dense network of “sentinels” that act as first line of defense of the immune system.1

There’s a lot of interest in using dendritic cells as vaccines these days.  A paper in PLoS One² offers a cautionary note.

Dendritic cells (DC) are the main cell type that drive T cells from their normal naive state to an active state.  In the naive state, a T cell can recognize its target, but doesn’t do anything about it; in the active state, the T cell does something, ranging from spreading inflammation to killing infected cells, and so on.  The DC is needed to bridge these states.  DC do many things, but at the simplest level they connect  the presence of an antigen (a T cell target, in this case) with the presence of something dangerous or abnormal — a pathogen, or tissue damage.

There are some conditions where we’d like an immune response, where DC don’t detect one or the other of their components (i.e. antigen or danger).  For example, there may be a situation that we know is dangerous, but where there’s  little evidence of “danger” for the DC.  A vaccine, for example, doesn’t want to deliver a huge amount of tissue damage, but we’d still like to get a strong response to an antigen.  For a natural situation, cancers are often ignored by the immune system even though there may be lots of cancer antigens, and one reason (of many) for this ignorance is that the DC may not perceive a lot of danger in the context of the cancer.

So why not take the DC out of the system, alarm them with some danger information in the test tube, load them up with antigen, and then return them to the body? That’s called a dendritic cell vaccine, and there’s fairly intense interest in the approach.

There’s been some success using this approach, but perhaps less than you’d expect from the biology as we understand it.

Several clinical trials conducted over the past decade have demonstrated that DC vaccines can prime and boost antigen-specific CD8+ T cells in humans. However, their clinical efficacy remains to be definitively demonstrated [6], [19], [20], [21]. The lack of success has been variously attributed to several factors: administration of relatively low cell numbers of DCs, suboptimal route of administration, improper antigen dose, poor choice of antigenic targets, unsuitable maturation state of DCs, and inappropriate frequency of injections. However, understanding exactly which of these concerns represent true problems may be difficult because little is known regarding the fate and function of ex vivo generated DCs after they have been injected ²

Yewdall et al asked what happens to DC after they’re given this course and returned to the patient (mice, in this case).  Their surprising conclusion is that the DC don’t work to prime T cells directly.  Instead, they have to hand off their antigens to other cells in the body that have never left:

Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. … This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs. ²

As always in science, a single paper needs to be confirmed by others, so we won’t get too distressed until we see if other groups replicate this, and if it’s a universal truth or something specific to the particular system these authors were looking at.  (And, of course, this doesn’t trump actual evidence of efficacy for DC vaccines.) My own suspicion is that the work is accurate but limited, and there’s something about this particular system which prevented the transferred DC from being good primers; but as I say, I’d like to see some followup from another group.

1. Tolerogenic dendritic cells and regulatory T cells: A two-way relationship. (2007) Karsten Mahnke, Theron S. Johnson, Sabine Ring and Alexander H. Enk. J of Derm Sci 46:159-167 doi:10.1016/j.jdermsci.2007.03.002 [↩]
2. Yewdall, A., Drutman, S., Jinwala, F., Bahjat, K., & Bhardwaj, N. (2010). CD8+ T Cell Priming by Dendritic Cell Vaccines Requires Antigen Transfer to Endogenous Antigen Presenting Cells PLoS ONE, 5 (6) DOI: 10.1371/journal.pone.0011144[↩][↩][↩]

Yeah, when I said the blog might have some hiccups as I transition from Michigan State to the CDC, I wasn’t really expecting them to be this large.

Part of the problem is that I’m doing a ton of influenza reading, and I’m reluctant to talk much about influenza here. Maybe that doesn’t make much sense, but I don’t want this to be in any way an “official” blog. I also worry a little about inadvertently talking about unpublished and premature stuff. Still, I’ll probably have some flu stuff here as I get a better grasp on the field.

I usually don’t like to give brief pointer-type posts, but I think that’s what I’m going to try for a little while — short posts pointing to recent papers that have caught my eye, without the background and context I usually try to include, but that I don’t have time (or mental energy) for right now.

Besides catching up on the flu field and preparing to drive down to Atlanta next week to start at the CDC, some other things that are keeping me busy at the moment:

• Finding landing spots for my students. I think we now have found labs and projects for all of them. One will move to the CDC with me and take up a flu project, while remaining an MSU student.  This has all taken a certain amount of paperwork and planning
• Playing catch with my kids in the back yard
• Trying to rearrange my grants. I don’t know if it is possible but I have proposed a new consortium and principal investigator to take over some of them
• Planning the future of my ongoing research projects.  Some will stay at MSU; one will probably move to a group of collaborators
• Arranging a temporary place to stay in Atlanta; looking for a permanent house in the Atlanta area
• Taking my kids to their baseball games (Monday/Wednesday – William; Tuesday/Thursday: Matthew; Friday – makeup games for both). I’m an  ”assistant coach”, which means I tie shoelaces, rig up catcher’s gear, and act as 3rd base coach when I’m not doing the more important shoelace-tying jobs
• Preparing our house here for sale.  Anyone want a lovely home in the East Lansing area? Crayon stains on the carpets will be removed, unless buyer likes the dramatic effect
• Co-ordinating plans with our movers. This is arranged through the government and takes a certain amount of paperwork
• Writing part of a book chapter on influenza
• Working on papers with co-authors. I play a minor role in 3 or 4 papers in press and submitted
• Preparing 3 of my own papers. Two are very close (waiting for replicates on data for the final figures); one could be done but needs to wait for one of the others to be in press before I submit it
• Throwing a goodbye party for our friends here.  Going to goodbye parties thrown by our friends here
• Preliminary exams. I’m on a bunch of students’ thesis committees, and one or two have arranged their qualifying exams to catch me before I go
• Taking my kids to Lansing Lugnuts (our local Single-A baseball team) games
• All the government paperwork involved in starting in the CDC.  There is a lot, and none of it is Mac-compatible, whereas I have no Windows computers available. Hmm.
• Going to our kids’ school for their end-of-year plays, performances, and parties. (Rainforest party this afternoon in Matthew’s class!)

There’s a lot more, but you get the idea.  My kids get off school this Friday, and I plan to spend the next week mostly hanging out with them, so I want to get as much paperwork and so on out of the way this week.

Anyway, I hope I’ll be able to get back into some posts, even if they’re relatively terse, soon.

We know that we need to make new vaccines against influenza each year, because new flu strains arise and spread each year and the previous year’s vaccines don’t give protection against the new strains.  Of course, there’s intense research toward developing cross-protective vaccines.  Ideally, flu vaccines would work like measles vaccines — get a shot as a child, be protected throughout life. That may not be a practical goal, but it’s a theoretical target.  More practically, even being able to vaccinate every five years or so would be a big step forward.    It’s clearly not going to be easy, though.  Natural infections don’t particularly offer a lot of cross-protection, and it’s hard¹ to get vaccines that induce a stronger immune response than the natural infection.

The pandemic H1N1 influenza last year was an interesting test ground to see how much, if any, cross-protection seasonal influenza vaccines gave.  Unfortunately the results have been pretty confusing, with different studies finding some cross-protection, no cross-protection, or even some increased risk.

The increased risk thing has been hashed out quite extensively already, so if you follow flu stories much you’ve undoubtedly already seen it. This is from the Canadian study² that found  that people vaccinated against flu in previous years –that is, against different flu strains — were somewhat more likely to get severe flu.

No one understands that finding, I think.  (The article itself is open-source, and there’s an excellent commentary on it³ here that’s also open-source, so check it out yourself.)  No one has been able to find any concrete problem with the study, other than its general nature — observational rather than randomized case/control.   But it’s clearly an outlier: Other studies looking at the same thing either find no effect either way, or a modest protective effect.

The latest in the series is a US Army study⁴ (open source, you can read it yourself) that finds a moderate protective effect of previous flu vaccinations against the pandemic H1N1 (pH1N1):

Our data also suggests that prior receipt of TIV [trivalent inactivated vaccine: IY] or LAIV [live attenuated influenza vaccine: IY] induces an association of protection against pH1N1-associated illness. This may reflect “priming” of the humoral immune system with influenza vaccine as demonstrated in immunologically-naïve children. … Additional findings from our study support the notion that vaccination with seasonal influenza vaccines in the preceding four years (2004–08) also conferred a certain degree of protective immunological memory relevant to the new viral strain. … Thus, it is reasonable to think that CMI [cell-mediated immunity: IY] plays a significant role and that cross-protective CMI to pH1N1 virus may actually exist in individuals who have been frequently immunized and/or exposed to seasonal influenza. ⁴

You always need to be a little cautious extrapolating army findings like this to the rest of the population. Military populations tend to be more crowded, more stressed, younger, fitter, and more homogeneous than the rest of the population. The vaccination rate among the service members in this study, for example, was much higher than in the general population.  There are a number of other possible sources of confusion that the authors carefully list. And of course, this is again an observational study, not a randomized prospective one.

But in the big picture, it (and similar studies) really do suggest that some cross-protection is possible in a natural population.  That’s really encouraging, because it shows there’s at least a foundation to build on for broadly cross-reactive vaccines.

1. Though not impossible[↩]
2. Skowronski, D., De Serres, G., Crowcroft, N., Janjua, N., Boulianne, N., Hottes, T., Rosella, L., Dickinson, J., Gilca, R., Sethi, P., Ouhoummane, N., Willison, D., Rouleau, I., Petric, M., Fonseca, K., Drews, S., Rebbapragada, A., Charest, H., Hamelin, M., Boivin, G., Gardy, J., Li, Y., Kwindt, T., Patrick, D., Brunham, R., & , . (2010). Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada PLoS Medicine, 7 (4) DOI: 10.1371/journal.pmed.1000258[↩]
3. Viboud, C., & Simonsen, L. (2010). Does Seasonal Influenza Vaccination Increase the Risk of Illness with the 2009 A/H1N1 Pandemic Virus? PLoS Medicine, 7 (4) DOI: 10.1371/journal.pmed.1000259[↩]
4. Johns, M., Eick, A., Blazes, D., Lee, S., Perdue, C., Lipnick, R., Vest, K., Russell, K., DeFraites, R., & Sanchez, J. (2010). Seasonal Influenza Vaccine and Protection against Pandemic (H1N1) 2009-Associated Illness among US Military Personnel PLoS ONE, 5 (5) DOI: 10.1371/journal.pone.0010722[↩][↩]

I’ve mentioned a couple of times recently that I’ve had some distractions in real life.  They’ve reached a level of confidence that I may as well explain them here.  Short version: I’ve had a job offer from the CDC, and I’m probably almost certainly going to leave my position at Michigan State University and join the CDC in Atlanta in the near future.

In handy pretend-question-and-answer format:

What’s the job? My title will be something like “Head of the Influenza Pandemic Preparedness and Vaccine Team“.  Being a government job, it probably sounds rather grander than it is. It’s a small to mid-sized research team  that covers various aspects of influenza pathogenesis, virology, and surveillance, focusing mainly but not only on the non-standard (i.e. non-seasonal) flu strains.

Why are you leaving MSU? I don’t think of it as “leaving MSU”, but rather as “going to the CDC”.  What I mean by that is that I’m very happy at MSU, it’s a great place, my research is going reasonably well, we are very fond of Michigan, and so on.  The only reason I’m changing positions is that I think the CDC position is going to be even more exciting and interesting.  And yes, I’m aware that I’m incredibly fortunate to be able to choose between these two wonderful opportunities.

When are you going? I’m probably moving in mid-June.

Do you have ten thousand and one things to do before then? Yes.

Are you looking forward to summers in Atlanta? No.  I’m Canadian.  I don’t deal well with heat.

What about this blog? There may be some hiccups as I have to worry about moving, selling and buying houses, and learning a bunch of new stuff.  But overall, I think it should keep going.

A majority of the epidemiological articles on SARS were submitted after the epidemic had ended, although the corresponding studies had relevance to public health authorities during the epidemic.  … although the academic response to the SARS epidemic was rapid, most articles on the epidemiology of SARS were published after the epidemic was over even though SARS was a major threat to public health. ¹

(My emphasis) This is an analysis of the published response to the SARS epidemic in 2003.   The conclusion is basically that, although SARS papers were clearly fast-tracked by journals, most papers didn’t see publication until after the epidemic was over.

They suggest that journals could speed up their fast-track systems for this sort of thing, and cite some of the subsequent attempts to speed up availability of publications (Nature Proceedings, Pandemic Flu Updates from the BMJ, and PLoS Current: Influenza), but point out that it’s not solely up to the journals: Most of the articles they looked at weren’t even submitted until the epidemic was over.  They suggest that authors could speed up data-collection and analysis:

This bottleneck could be reduced by developing a series of ready-to-use information technologies, to improve timeliness and, thus relevance, and further, to improve standardization, and thus comparability across studies in the event of an outbreak.¹

That presumably means that epidemiologists should, right now, be preparing tools for the next pandemic.  I assume some are, but I don’t know how widespread that is.

I’d be very interested to compare the 2003 SARS response to the 2009/2010 pandemic flu response.  My impression was that the response was much faster — not only through the fast-tracked sites mentioned above, but through semi-formal channels as well.  Though it wasn’t a target of this paper (which focused on peer-reviewed papers) I’d also be interested to see how much (if any) impact blogs had for the flu response.

1. Xing, W., Hejblum, G., Leung, G., & Valleron, A. (2010). Anatomy of the Epidemiological Literature on the 2003 SARS Outbreaks in Hong Kong and Toronto: A Time-Stratified Review PLoS Medicine, 7 (5) DOI: 10.1371/journal.pmed.1000272[↩][↩]

I was getting a little concerned and distressed by the lack of evidence for any function of viral MHC class I immune evasion. It’s kind of a relief to see articles demonstrating function coming out.

MHC class I is the target for cytotoxic T lymphocytes (CTL), which are generally believed to be pretty important in controlling viral infection. So when some viruses were shown to block MHC class I in cultured cells, it seemed pretty obvious that this would be a big benefit for the virus. You’d expect these viruses to be exceptionally resistant to CTL, for example.

But when people actually looked in animals (as opposed to in tissue culture), the ability to block MHC class I didn’t seem to do all that much. I’ve summarized some of those experiments here and here. For example, the MHC class I immune evasion genes in adenoviruses and in mouse cytomegalovirus (MCMV) didn’t show much effect on the actual infection at all.¹ Mouse herpesvirus 68 (MHV68) had shown an effect, but not at the time point that you might expect — not early after infection, when CTL are kicking in and clearing virus, but rather later on, during the latent phase.²

We all believed there must be a function, because viruses don’t hang on to genes for millions of years unless those genes are important,³ but I was starting to wonder if perhaps we were looking in the wrong places — whether any immune effects might be spillover from some other function, say. But, as I say, we’re starting to get confirmation that these things really are doing more or less what we’d expected all along.

A little while ago, Klaus Fruh and Louise Pickert showed a significant effect of MHC class I immune evasion in rhesus cytomegalovirus: without that ability new viruses couldn’t superinfect hosts that already carry the virus. ⁴ (I talked about it here.) It’s quite possible — though of course not certain until it’s actually tested — that this is also true for human cytomegaloviruses (which are very closely related to the rhesus version) and for mouse CMV (which are less closely related but in the same family). So now we have functional data for MHC class I immune evasion for representatives of two broad groups of viruses, the betaherpesviruses (the cytomegaloviruses) and the gammaherpesviruses (the MHV68 story).

Now there’s another paper⁵ showing a function for the MHC class I immune evasion ability of HIV (actually for SIV, but again it’s probably true for the closely-related HIV).

HIV has a gene, nef, that can block MHC class I expression. This has been shown in cultured cells, but understanding its relevance in actual infections has been difficult:

Although these data suggest that Nef-mediated immune evasion could play an important role in AIDS pathogenesis, there has been little direct evidence linking disease progression with MHC-I downregulation in vivo. ⁵

Obviously you can’t make a nef-less HIV and just throw it into people to see what happens. Even doing the experiment in monkeys with SIV is complicated by the fact that nef is very polyfunctional — as well as downregulating MHC class I, it also targets a number of other molecules.

But you can take advantage of natural variation, both in the virus and the host.  Nef isn’t equally effective on all MHC class I types, for one thing. As well, nef can develop mutations within the host.  It turns out that rapid disease progression correlates with the extent of MHC class I downregulation, whereas effects on other genes affected by nef (CD3 and CD4) didn’t correlate:

The extent of MHC-I downregulation on SIV-infected cells varied among animals …  the level of MHC-I downregulation on SIV-infected cells was significantly greater in the rapid progressor animals than in normal progressors.  … high levels of MHC-I downregulation on SIV-infected cells are associated with uncontrolled virus replication and a lack of strong SIV-specific immune responses.⁵

This is strictly a correlation study, so we can’t confidently say that MHC downregulation causes disease progression. Still, it’s an interesting finding, and perhaps one that can be followed up in human studies.

1. Gold MC, Munks MW, Wagner M, McMahon CW, Kelly A, Kavanagh DG, Slifka MK, Koszinowski UH, Raulet DH, & Hill AB (2004). Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. Journal of immunology (Baltimore, Md. : 1950), 172 (11), 6944-53 PMID: 15153514
   Only slightly qualified by
   Lu, X., Pinto, A., Kelly, A., Cho, K., & Hill, A. (2006). Murine Cytomegalovirus Interference with Antigen Presentation Contributes to the Inability of CD8 T Cells To Control Virus in the Salivary Gland Journal of Virology, 80 (8), 4200-4202 DOI: 10.1128/JVI.80.8.4200-4202.2006[↩]
2. Stevenson, P., May, J., Smith, X., Marques, S., Adler, H., Koszinowski, U., Simas, J., & Efstathiou, S. (2002). K3-mediated evasion of CD8+ T cells aids amplification of a latent ?-herpesvirus Nature Immunology DOI: 10.1038/ni818[↩]
3. I will admit there’s a certain circular quality to this argument.  ”The gene must be important, because viruses don’t carry unimportant genes.  We know that, because this gene that they’ve hung on to must be important.”[↩]
4. Hansen, S., Powers, C., Richards, R., Ventura, A., Ford, J., Siess, D., Axthelm, M., Nelson, J., Jarvis, M., Picker, L., & Fruh, K. (2010). Evasion of CD8+ T Cells Is Critical for Superinfection by Cytomegalovirus Science, 328 (5974), 102-106 DOI: 10.1126/science.1185350[↩]
5. Friedrich, T., Piaskowski, S., Leon, E., Furlott, J., Maness, N., Weisgrau, K., Mac Nair, C., Weiler, A., Loffredo, J., Reynolds, M., Williams, K., Klimentidis, Y., Wilson, N., Allison, D., & Rakasz, E. (2010). High Viremia Is Associated with High Levels of In Vivo Major Histocompatibility Complex Class I Downregulation in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239 Journal of Virology, 84 (10), 5443-5447 DOI: 10.1128/JVI.02452-09[↩][↩][↩]

Malaria is an annual production of nearly every section of the United States. No State is entirely free from it. The Western States for well-known reasons, have gained considerable notoriety for the number and frequency of Malarial diseases within their borders. These diseases in Michigan, among natives, are of the mildest forms, much milder than those on the Chesapeake peninsula, to say nothing of the severer forms seen on the Virginia low lands, or in the Carolinas.

–Magnetic & Mineral Spring of Michigan,
to which is
Prefixed an Essay
on the
Climate of Michigan

by Stiles Kennedy, MD

James & Webb, Wilmington, Delaware