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.[]