MHC Restriction and Host-Pathogen Co-Evolution

This week marks the 35^th anniversary of the landmark paper, in Nature [248:701-702, 1974, April 19], by Rolf Zinkernagel and Peter Doherty that established the principle that T lymphocytes [murine cytotoxic T lymphocytes (CTL) in this study] exhibit specificity for both the nominal antigen (e.g. a gene product derived from a pathogen such as HIV-1 or influenza virus) and a self-major histocompatibility complex (MHC) molecule, a phenomenon that became known as “MHC restriction.” Zinkernagel and Doherty showed that only CTL from mice immunized with lymphocytic choriomeningitis virus (LCMV) and sharing MHC alleles with radioactively-labeled target cells could effectively lyse those target cells after they had been infected with LCMV. One element that made this discovery particularly noteworthy was that in a subsequent publication in Lancet [1975 Jun 28;1(7922):1406-1409], the two immunologists used MHC restriction to explain the high degree of polymorphism already documented for murine and human class I MHC loci.

In this context, it is of interest that a recent paper by Kawashima et al., in Nature [2009 Apr 2;458(7238):641-645], offers impressive evidence that the evolution of HIV-1 is shaped by the prevalence of particular human gene products, the HLA class I molecules encoded at the HLA-B locus. The phenomena being investigated were the ability of CTL to recognize a particular class I MHC molecule (sometimes referred to as a restriction element) that has nonocovalently bound a peptide derived from a protein encoded by the HIV-1 genome and the ability of HIV-1 to undergo mutation in the gene encoding the peptide leading to reduced recognition by the CTL and viral “escape.” Kawashima et al. focus particularly on a recurring escape mutation at position 135 [from isoleucine to one of several other amino acids (I135X)] of the HIV-1 reverse transcriptase that affects the recognition of the peptide when bound to (“presented by”) HLA-B*51. This mutation is shown in most cases (depending on the identity of the new amino acid) to decrease binding of the peptide to HLA-B*51 and to concomitantly reduce the effectiveness, as assessed in vitro, of CTL clones of relevant specificity.

The authors present data indicating that this mutation (i.e., I135X) tends to be more common in populations that have higher frequencies of HLA-B*51 and less common in populations that have lower frequencies of HLA-B*51. Several other peptides derived from HIV-1 gene products and presented by class I molecules encoded by various HLA-B alleles were shown to behave similarly. A possible outcome of this process would be that a relatively common HLA-B gene product would be associated with a decreasing net fitness contribution as the escape mutation frequency increases, perhaps leading ultimately to some reduction in the frequency of the corresponding class I MHC allele over time. Thus, the challenge of designing effective CTL-inducing HIV-1 vaccines could be increased by both viral epitope evolution and the dynamic changes in class I MHC allele efficacy in contributing to viral load control.

Multiple factors can add considerable complexity to these phenomena. First, some peptides can be effectively bound and presented to T cells by more than one class I MHC restriction element. Second, some, but not all, CTL escape mutations are associated with reduced viral fitness as best as we can assess it in vitro, and, correspondingly, some, but not all, escape mutations are prone to reversion in hosts lacking the relevant restriction element. Third, the consequences for viral intra-host evolutionary dynamics may differ depending on whether transmission occurs to a new host that does or does not express the restriction element(s) relevant for the particular peptide subject to the escape mutation. Fourth, different MHC class I alleles exhibit variation in the extents to which they are associated with effective CTL responses that contribute to control of HIV-1 replication.

Other recent papers from just the authors involved in the Kawashima et al. study have explored, for example, the relative extent of intra-host evolution in individuals expressing relatively rare versus relatively common HLA class I alleles (Rousseau et al., 2009), the patterns of viral evolution seen in the context of a particular class I allele, HLA-B*5703 (Crawford et al., 2009), and the overall impact of HLA variation on both intraclade and interclade HIV evolution at a population level (Matthews et al., 2009). Clearly, this research domain will not run out of interesting phenomena to characterize and important evolutionary mechanisms to elucidate anytime soon. Of particular interest would be more information on the impact of the HIV-1 epidemic on HLA-B locus allele frequencies in different human populations.

References

Zinkernagel RM, Doherty PC. (1974) Restriction of in vitro T cell-mediatedcytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 248(450):701-2.

Doherty PC, Zinkernagel RM. (1975) A biological role for the major histocompatibility antigens. Lancet 1(7922):1406-9.

Kawashima Y, Pfafferott K, Frater J, Matthews P, Payne R, Addo M, Gatanaga H, Fujiwara M, Hachiya A, Koizumi H, Kuse N, Oka S, Duda A, Prendergast A, Crawford H, Leslie A, Brumme Z, Brumme C, Allen T, Brander C, Kaslow R, Tang J, Hunter E, Allen S, Mulenga J, Branch S, Roach T, John M, Mallal S, Ogwu A, Shapiro R, Prado JG, Fidler S, Weber J, Pybus OG, Klenerman P, Ndung’u T, Phillips R, Heckerman D, Harrigan PR, Walker BD, Takiguchi M, Goulder P. (2009) Adaptation of HIV-1 to human leukocyte antigen class I. Nature 458(7238):641-5.

Rousseau CM, Lockhart DW, Listgarten J, Maley SN, Kadie C, Learn GH, Nickle DC, Heckerman DE, Deng W, Brander C, Ndung’u T, Coovadia H, Goulder PJ, Korber BT, Walker BD, Mullins JI. (2009) Rare HLA drive additional HIV evolution compared to more frequent alleles. AIDS Res Hum Retroviruses. 25(3):297-303.

Crawford H, Lumm W, Leslie A, Schaefer M, Boeras D, Prado JG, Tang J, Farmer P, Ndung’u T, Lakhi S, Gilmour J, Goepfert P, Walker BD, Kaslow R, Mulenga J, Allen S, Goulder PJ, Hunter E. (2009) Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients. J Exp Med. 206(4):909-21.

Matthews PC, Leslie AJ, Katzourakis A, Crawford H, Payne R, Prendergast A, Power K, Kelleher AD, Klenerman P, Carlson J, Heckerman D, Ndung’u T, Walker BD, Allen TM, Pybus OG, Goulder PJ. (2009) HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering. J Virol. 83(9):4605-15.