HIGHLIGHTS

NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | MAY 2004 | 317

HIGHLIGHT ADVISORS

CEZMI AKDIS

SWISS INSTITUTE OF ALLERGYAND ASTHMA RESEARCH,SWITZERLAND

BRUCE BEUTLER

SCRIPPS RESEARCH INSTITUTE,USA

PETER CRESSWELL

YALE UNIVERSITY, USA

JAMES DI SANTO

PASTEUR INSTITUTE, FRANCE

GARY KORETZKY

UNIVERSITY OFPENNSYLVANIA, USA

CHARLES MACKAY

GARVAN INSTITUTE OFMEDICAL RESEARCH,AUSTRALIA

CORNELIS J. M. MELIEF

LEIDEN UNIVERSITY MEDICALCENTRE, THE NETHERLANDS

MICHEL NUSSENZWEIG

THE ROCKEFELLER UNIVERSITY,USA

SARAH ROWLAND-JONES

CENTRE FOR TROPICALMEDICINE, OXFORD, UK

ALAN SHER

NATIONAL INSTITUTE OFALLERGY AND INFECTIOUSDISEASE, USA

ANDREAS STRASSER

THE WALTER AND ELIZA HALLINSTITUTE, AUSTRALIA

MEGAN SYKES

HARVARD MEDICAL SCHOOL,USA

ERIC VIVIER

CENTRE D’IMMUNOLOGIE DEMARSEILLE-LUMINY, FRANCE

MATTHIAS VON HERRATH

LA JOLLA INSTITUTE FORALLERGY AND IMMUNOLOGY,USA.

One way in which HIV can avoiddetection by the immune system is tomutate the protein epitopes that arepresented by infected cells on MHCclass I molecules to cytotoxic T lym-phocytes (CTLs). Philip Goulder andcolleagues have now shown for thefirst time in a natural human infectionthat HIV can also take an indirectroute to CTL escape by mutatingresidues outside of CTL epitopes thataffect antigen processing.

This study identified a polymor-phism at amino-acid residue 146(alanine to proline; A146P) of theHIV-1 protein Gag that is morecommon in patients expressing theMHC class I molecule HLA-B57.The authors show that the observedvariation at Gag residue 146 is theresult of selection pressure mediatedby HLA-B57. For example, inknown examples of wild-type HIVtransmission from an HLA-B57–

mother to an HLA-B57+ child, theA146P mutation arose subsequentto transmission in the child.

In HLA-B57+ individuals infectedwith HIV-1, the A146P mutation isassociated with a 22-fold increase inviral load compared with wild-typevirus, resulting in an increased risk ofprogression to AIDS. CD4+ T cellsfrom an uninfected HLA-B57+ donorthat were infected in vitro with a virusconstruct containing the A146Pmutation could not be lysed by CTLsspecific for the epitope ISW9, in con-trast to cells infected with wild-typevirus constructs. Surprisingly, how-ever, residue 146 does not lie within

ISW9 (Gag residues 147–155), butinstead is found immediately pre-ceding the amino terminus of thisepitope. The authors suggest that themutation at residue 146 affects thepathway by which proteins becomepresented on MHC molecules, andtherefore indirectly affects CTL recog-nition, because the unmutated epi-tope itself never reaches the surface ofthe cell.

In support of this, the endo-plasmic-reticulum aminopeptidaseERAP1 could not cut amino-terminal-extended ISW9 peptides that con-tained proline, rather than alanine, atresidue 146. ERAP1 is involved in anti-gen presentation by trimming peptideepitopes to the correct length to bindMHC class I molecules, so the failureof A146P-containing peptides to be

trimmed could result in poor pre-sentation on the surface of HIV-infected cells and therefore poorCTL recognition and killing.

This indirect mechanism of CTLescape has been postulated by manyresearchers on the basis of artificialmutation studies, but this is the firsttime that it has been shown to occurnaturally. The research has impor-tant implications for vaccine designas it indicates that the residuesbetween epitopes are also crucial foran efficient CTL response.

Kirsty MintonReferences and links

ORIGINAL RESEARCH PAPER Draenert, R. et al.Immune selection for altered antigen processingleads to cytotoxic T lymphocyte escape in chronicHIV-1 infection. J. Exp. Med. 199, 905–915 (2004)FURTHER READING Phillips, R. E. Immunologytaught by Darwin. Nature Immunol. 3, 987–989(2002)

HIV takes the indirect route

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