Mystery Rays from Outer Space

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

August 2nd, 2007

Immunodominance, Part II: Why care?

HIV budding from a lymphocyteHIV and hepatitis C virus (HCV) are the two best-known chronic infections of humans. Both of them seem to persist at least partly by throwing out immune escape variants.

To expand that a bit: These are viruses that continue to infect people in spite of a specific immune response: People infected with either virus, generate cytotoxic T lymphocytes (CTL) that recognize and destroy infected cells. CTL recognize short peptides, say 9 amino acids long, that are derived from viral proteins. If you monitor which viral peptides that CTL are recognizing, and track those peptides over time, what you often (but not invariably) find is that the peptides in the dominant virus in the body changes sequence over time. As a result, CTL regularly lose the ability to recognize the virus. Each time (at least for a while) the virus mutates away from the CTL, new CTL pop up that recognize the new version of the virus, but each time the virus has a window to bump up its replication for a while as CTL control is reduced. 1

This sort of immune escape occurs in HCV infections as well2 although it’s not as clear that it’s critical to HCV persistence:3

Although it is clear that CTL escape mutations occur in HCV genomes, the relevance of this mechanism to viral persistence is an open question. Mutations usually occur within the first 3-4 months of infection …. Such observations are compatible with release from early immune selection pressure as viral escape is established, and perhaps suggest a role for CTL escape mutations in the genesis of chronic infection.

Boat wakePicture the virus as motorboat, roaring through the T cell ocean, leaving behind it a wake of failed CTL that can no longer recognize the viral epitopes. The problem with this image is that to keep ahead, the virus has to continually change its sequence4 and changing a protein’s sequence usually means losing some functionality. It’s been shown that immune escape is often associated with a reduction in viral fitness.5 From any particular viral sequence, there are probably a limited number of directions the virus can move without losing its ability to replicate effectively: “The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.”6

So it’s not as effortless as it seems for the persistent virus to keep on mutating away from the controlling T cells; the virus takes a pretty big hit to do so. The amount of fitness the virus is “willing” to lose in order to escape from CTL recognition tells us just how effective CTL must be in controlling the virus, so CTL must be pretty good at the job. How can we help CTL control the virus? How can we keep the virus from escaping from CTL control?

This is where the concept of immunodominance comes in (see? I had a point after all!). Immunodominance, if you missed the last post on the subject, is the observation that (for reasons that are not well understood) immune responses often focus on a very limited number of epitopes; there may be many peptides that are recognized to some extent, but the vast majority of CTL recognize only two or three of those peptides. If a CTL response is “broad”, meaning that many viral epitopes are recognized well (with no clear immnodominant epitope), then to escape from CTL control the virus quasispecies must throw out multiple mutations at the same time. That’s much harder (less likely) than throwing out a single mutation; and it’s much harder than sequentially throwing out single escape mutants, with periods in between of efficient replication (unchecked by CTL) in which the quasispecies can establish compensatory mutations and become set for a new mutation.

In this context, then, immunodominance may be a bad thing. It’s been suggested7 that some individuals who can control HIV for a long time, do so at least partially because of their subdominant CTL response. If we could manipulate the CTL response during vaccination or initial infection, then, perhaps we could reduce the response to an immunodominant epitope and increase the responses to multiple subdominant epitopes, and perhaps this would help control HIV infection.

Is there a context in which immunodominant responses are good things?

More later.

  1. I think the first paper showing evidence for HIV immune escape was Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Rodney E. Phillips, Sarah Rowland-Jones, Douglas F. Nixon, Frances M. Gotch, Jon P. Edwards, Afolabi O. Ogunlesi, John G. Elvin, Jonathan A. Rothbard, Charles R. M. Bangham, Charles R. Rizza & Andrew J. Mcmichael. Nature 354, 453 – 459 (12 December 1991) []
  2. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Erickson AL, Kimura Y, Igarashi S, Eichelberger J, Houghton M, Sidney J, McKinney D, Sette A, Hughes AL, Walker CM. Immunity. 2001 Dec;15(6):883-95. []
  3. Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. David G. Bowen and Christopher M. Walker. J Exp Med 201: 1709-1714 (6 June 2005) []
  4. To be a little more accurate, there’s no single “virus”, but rather a cloud of viruses with slightly varying sequences — a quasispecies; within that cloud, the majority may have the immune-escape sequence.[]
  5. For example: Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost. Fernandez CS, Stratov I, De Rose R, Walsh K, Dale CJ, Smith MZ, Agy MB, Hu SL, Krebs K, Watkins DI, O’connor DH, Davenport MP, Kent SJ. J Virol. 2005 May;79(9):5721-31.[]
  6. Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. Allen TM, Altfeld M, Geer SC, Kalife ET, Moore C, O’sullivan KM, Desouza I, Feeney ME, Eldridge RL, Maier EL, Kaufmann DE, Lahaie MP, Reyor L, Tanzi G, Johnston MN, Brander C, Draenert R, Rockstroh JK, Jessen H, Rosenberg ES, Mallal SA, Walker BD. J Virol. 2005 Nov;79(21):13239-49.[]
  7. For example, Subdominant CD8 T-Cell Responses Are Involved in Durable Control of AIDS Virus Replication . Thomas C. Friedrich, Laura E. Valentine, Levi J. Yant, Eva G. Rakasz, Shari M. Piaskowski, Jessica R. Furlott, Kimberly L. Weisgrau, Benjamin Burwitz, Gemma E. May, Enrique J. Leon,Taeko Soma, Gnankang Napoe, Saverio V. Capuano III, Nancy A. Wilson,and David I. Watkins. J Virol, Apr. 2007, p. 3465-3476 Vol. 81, No. 7 doi:10.1128/JVI.02392-06; and Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes. Frahm N, Kiepiela P, Adams S, Linde CH, Hewitt HS, Sango K, Feeney ME, Addo MM, Lichterfeld M, Lahaie MP, Pae E, Wurcel AG, Roach T, St John MA, Altfeld M, Marincola FM, Moore C, Mallal S, Carrington M, Heckerman D, Allen TM, Mullins JI, Korber BT, Goulder PJ, Walker BD, Brander C. Nat Immunol. 2006 Feb;7(2):173-8.[]
August 1st, 2007

Software special

My computer was having intermittent hard drive problems, and last week they got bad enough that I sent the Macbook Pro off for repair (free under warranty). The good news is they fixed it, as far as I can see; the bad news is they dropped in a new hard drive, so I’m starting from scratch.

I’m pretty paranoid about backups (four times a day, to external drives in two different locations) so I didn’t lose any significant dat. The problem when this happens (the second time in a couple years) or when I get a new computer, is that I have to reload all the third-party applications I use; and that means figuring out what I need, finding them on the net, reinstalling, finding registration numbers in my saved mail, and so forth.

To save myself some time next time this happens, I’m noting down the apps I’ve reinstalled this time. And in case anyone else cares, here they are.

Commercial apps.

Photoshop I hardly ever use this, but it’s nice to have on hand
BookEnds Reference and bibliography software. Much better than EndNote
DNA Strider DNA/protein analysis and enzyme mapping. There are probably better free products out there, but 17 years of finger memory is hard to quit
Flowjo Flow cytometry analysis. Registration is tied to the computer, need to update via the company
iWorks Pages and Keynote from Apple. I don’t know if I’m actually going to reinstall this, I hardly ever use it
MS Office Word,Excel, PowerPoint. Yes, I’ve tried the free alternatives. No, I don’t like them.

Freeware, donationware, and shareware.

Free- & shareware
4Peaks DNA Sequencing reader
Adium Instant messaging client for AIM, Jabber, MSN, Yahoo
Adium themes “Old Phone” dock icon
“A Little Less Than Minimal” contact list
“Good Grey” message style
Big Cat Scripts Contextual menu applescripts. Very useful and customizable
AppleWorks I still have one legacy database in this that I haven’t transfered to SQLite
CyberDuck FTP/sFTP
EnzymeX DNA/Protein analysis. I should probably use this instead of Strider, but old habits die hard
FastScripts Lite Menubar access to Applescripts. Not much difference from the builtin scripts folder
Firefox Not my default browser right now, but useful for some things
Firefox extensions Adblock Plus
Adblock Filterset
Quick Proxy
Download Statusbar
Gleam Flickr uploader
Google Earth  
Google Hosted Mail Notifier Menubar notice when I get new mail in my hosted gmail
Growl System notifications, integrated with several other apps. Also remember to install growlnotify
Journler I haven’t paid for this yet but probably will soon. Flawed, but better than the other organizers/notebooks I’ve tried.
JungleDiskMonitor For my Amazon S3 account. Still in beta. I will probably pay for it when it’s out of beta, but haven’t decided for sure yet
Magic Number Machine Stupid name and dock icon, but a good scientific calculator
MagiCal Customize menu time and date display
MenuMeters Menubar CPU use, also quick access to the Console
PandoraMan For the Pandora Streaming Radio service, which kicks ass
Safari 3 My default browser on Intel Macs, though it was less stable on PowerPC macs. Faster and smoother than Safari 2
ServiceScrubber Eliminate crap from the Service menu, so you can find the few services that are actually useful
SlimBatteryMonitor Uses less space in the menubar than the builtin battery monitor
Stuffit Horrible company, but I still need the expander occasionally
Synergy iTunes monitor and controller. I got a license for this years ago when it was by far the best controller, now competitors (including freeware) are catching up
Synk 5 Backup software. I use it a lot. (The latest version is 6, but I wasn’t impressed by it and already have a licence for the previous version so stuck with v.5)
TextWrangler Programming editor. Nothing else I’ve tried has been as versatile.
Vienna RSS reader
VLC Video viewer
WeatherMenu Weather in the menubar. Now freeware, but I got a licence many years ago when it was by far the best available – now there are competitors that are close
Windows Media Player I used to need this for baseball highlights and listening to games on MLB’s stream. Don’t know if I still need it, but hey.
X11 Apple’s verions of the X window system
XJournal Livejournal blogging client
XCode Apple Developer Tools
XMenu Menubar access to apps. There are a million different apps for this, this is just as far as I got before I found one I was comfortable with

Programming in Python. Apple includes Python2.3 and wxPython2.6 (or so), which are a few versions back of the latest. I update to Python2.4 (the latest is 2.5, which I haven’t moved to yet) and the latest wxPython (2.8.4 as of now).

Python/modules Comments
Python2.4 Programming language. Packaged for OSX here
wxPython2.8.4 For GUI integration
NumPy Numeric modules. OSX package
PySQLite SQLite database API. OSX package
Python Imaging Library (PIL) OSX package
ElementTree XML parsing
mxBase tools Required for BioPython
py2app Turn Python scripts into standalone apps
PyObjC Python/Objective C bridge
appscript Manage apple events with Python (just like Applescripts)
BioPython Many bioscience-related modules
DarwinPorts Unix-type apps ported to Darwin. I don’t use this just for Python, but it fits here better than elsewhere, I guess.

Dashboard widgets. I used to use widgets a lot, but have gradually moved away. I still use some of these regularly, though.

Widgets Comments
Reminder Widget Minimalist reminders (uses growlnotify). I wrote this one
Translate Widget DNA formating, translation, analysis. I wrote this one too
Digital World Clock Know the time for my sister in Switzerland and my brother in Beijing
Flip Clock Widget A clock for local time
iCal Events Widget Upcoming events from iCal
Scoreboard Widget Red Sox game tracking. Like I don’t already have it on the radio
AlbumArt Widget iTunes track indicator, with album art
PEMDAS Widget Calculator widget
Package Tracker Track FedEx, UPS, DHL pacakges

Applescripts for /Library/Scripts. These are just things I slapped together myself; here to remind myself to migrate them over. If anyone cares I can make them available, but they’d likely need tweaking for general use.

Applescripts Comments
File from Safari URLs Save the URLs from all open tabs into a text file
File to Safari URLs Open URLs from a text file into Safari
URLs -> Journler Save URLs from all opens tabs into Journler
Journler URLS -> Safari Open all URLs from a Journler page in Safari
Format Excel Chart Why doesn’t Excel let you save a default chart format? This makes the half-dozen formating changes I invariably set
Format sequence Take a DNA orprotein sequence, make a tidy numbered output
Images size adjust Quickly adjust the size of selected images
Strip sequence Remove all non-DNA characters (including spaces and newlines) from a DNA sequence
Track -> XJournal XJournal reads iTunes tracks, but doesn’t format classical properly. This is a fix for classical tracks

Finally, remember to copy back:

Files Comments
~/Library/Keychains/login.keychain Don’t lose your passwords
~/.bash_profile Terminal shortcuts and formats
~/.pythonstartup Python preferences