Recent Advances in HIV-1 CTL Epitope Characterization

Christian Brander and Philip J. R. Goulder

Updated November 1999

Since the last update of the Los Alamos HIV Immunology Database in 1998, the role of CTL in HIV and SIV infection has been further recognized as a beneficial and essential part of the host immune response against these viruses [Schmitz(1999), Brander & Walker(1999b)]. As the full picture of the precise role of HIV specific CTL is still emerging, it becomes clear that under certain circumstances these cells are able to contribute significantly to the control of viral replication in infected individuals [Ogg(1998)]. Along with more sophisticated techniques to detect and quantify CTL responses, including ELISPOT and Tetramer methodologies [McMichael & O'Callaghan(1998), Goulder(2000a)], more detailed analyses of the genetic background of infected individuals may provide new insights into HIV pathogenesis [Tang(1999), Carrington(1999)].

The identification of HLA alleles which are associated with more rapid or slower disease progression, may now be linked to the importance and dominance of certain CTL epitopes. It is intriguing that thus far, only HLA-B alleles have been consistently associated with HIV-1 disease progression, which may be due to the relative distance of HLA-A genes to the central part of the MHC region containing HLA class III genes involved in the antigen processing. It is interesting that for some alleles (e.g. HLA-A1) no optimal epitopes have been defined, despite relative high frequencies in diverse populations. The mechanisms for HLA association and disease progression and the pattern of class I alleles that present HIV-derived CTL epitopes, including HLA alleles that are frequent in non-Caucasoid populations, require further investigation and these results will also need to be considered for the design of (epitope based) vaccines.

The current update of the list of optimal CTL epitope has undergone a few improvements:

There are an increased number of epitopes listed and the nomenclature for the HLA alleles has been updated. Accordingly, the order of the epitopes may have changed slightly: e.g. the `HLA-B62' allele is now listed as HLA-B*1501. The data for the HLA class I binding motifs have been added for as many HLA alleles as possible and are mainly based on the database by Rammensee and co-workers [Rammensee(1999)].

This year's update has also been modified as more attention was given to epitopes that were contributed by personal communication. The individuals who kindly submitted their unpublished epitopes over the last few years were asked for more detailed titration/truncation data. We have now highlighted with an asterisk (*) those epitopes contributed as personal communications for which we had a chance to review the titration data. As a consequence of this enhanced scrutiny, a number of epitopes (mainly from our own laboratories) had to be removed from the list of optimal epitopes since the characterization did not fulfill all the stricter inclusion criteria. We would like to define these inclusion criteria still further as: a) detailed HLA restriction, possibly including subtype analysis; and b) titration curves with single amino acid truncated, longer and shorter versions of the epitope. In this regard, we found that titration curves with truncated peptides can easily be performed by ELISPOT, even at low numbers of CTL clones added per well (M. Altfeld, unpublished). In addition, an HLA-B35 restricted epitope in gp120 reported by Shiga et al., [Shiga(1996)], was included without peptide titrations being performed, since it has been used successfully in tetramer staining procedure in later studies [Ogg(1999)].

Some of the newly added epitopes deserve special attention as these are the first ones of a series of epitopes that have been identified in individuals with acute HIV-1 infection (M. Altfeld, unpublished data). These preliminary studies suggest that responses which are immunodominant in acute infection may differ from those seen in chronic infection. These findings will need more confirmation, but may also help to explain the immunodominance of certain epitopes in chronic infection. One possible explanation for these different responses could be that the responses elicited during acute infection are diminished over time (for various reasons, [Brander & Walker(1999b)] and that a new generation of epitopes that may be more resistant to CTL escape remain detectable in chronic infection. In this regard, the clustering of CTL epitopes to certain regions of the HIV genome may need to be revisited and more studies in acute infected individuals may help to complete the picture of the role CTL play in HIV infection.

We would like to express our gratitude to the large number of researchers in the field who continuously contribute to this database. We very much welcome any criticism, comments and additions to this list since we are sure that some epitopes will unintentionally escape our attention, despite close monitoring of the literature. Please write or call us with any comments at:

Christian Brander 			Bruce D. Walker 
phone: (617) 724-5789 			phone: (617) 724-8332 
FAX:   (617) 726-5411 			FAX: (617) 726-4691
brander@helix.mgh.harvard.edu 		bwalker@helix.mgh.harvard.edu

Philip J.R. Goulder 			Bette Korber 
phone: (617) 726-5787 			phone: (505) 665-4453 
FAX:   (617) 726-5411 			FAX: (505) 665-3493
goulder@helix.mgh.harvard.edu 		btk@t10.lanl.gov 

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[Goulder (2000a)]
P.J.R. Goulder, C.Brander, K.Annamalai, N.Mngqundaniso, U.Govender, Y.Tang, S.He, K.E. Hartman, C.A. O'Callaghan, G.S. Ogg, M.A. Altfeld, E.S. Rosenberg, H.Cao, S.A. Kalams, M.Hammond, M.Bunce, S.I. Pelton, S.A. Burchett, K.McIntosh, H.M. Coovadia, &B.D. Walker. Differential narrow focusing of immunodominant HIV gag-specific CTL responses in infected African and Caucasoid adults and children. submitted 2000a.

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P.Shankar, J.A. Fabry, D.M. Fong, &J.Lieberman. Three regions of HIV-1 gp160 contain clusters of immunodominant CTL epitopes. Immunol Lett 52:23--30, 1996.

[Shiga (1996)]
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