peptides that bind to hla b27 almost always have an arginine ( r ) at the second position , which fits snugly into the b pocket of the peptide - binding groove of the hla molecule . the arginine at position 264 in the hiv-1 gag epitope is encoded by the amino acid codon aga ( or more rarely , agg ) . the single mutations that have been recorded at this codon include aaa ( lysine ) , aca ( threonine ) , and gga or agg ( glycine ) . although peptides with these substitutions may bind sufficiently to hla b27 in in vitro assays , they are not recognized by t cells when expressed within the cell as viral or transfected sequences ( 8) . given the high replication and mutation rates of hiv-1 , one might expect the virus to escape rapidly and completely from the early t cells that recognize this epitope . escape from this epitope , however , typically occurs only after several years , happening in at least 50% of hla b27 patients who are studied for several years ( 3 , 11 , 12 , and unpublished data ) . according to the los alamos hiv sequence database , these mutations are very rare in the general population of hiv - infected individuals ( 7 ) , who showed that the critical arginine - to - lysine change at position 264 ( r264k ) only occurred when there had been a previous change of leucine - to - methionine at position six in the epitope ( l268 m ) . unlike the arginine at position 2 , the side chain at position 6 is not involved in hla b27 binding but rather faces and interacts with the t cell receptor ( fig . 1 ) . more recently , schneidewind et al . ( 4 ) showed that there is nearly always a third amino acid change that accompanies the r264k and l268 m mutations : an alanine - to - serine change at position 173 ( a173s ) . this amino acid lies outside the epitope , but the three mutated amino acids cluster in the three - dimensional structure of p24 , suggesting that they might compensate for each other . the r264k mutation imparts a fitness cost on the virus , as elegantly shown by goulder et al . ( 2 ) , who found that the virus rapidly mutated this sequence back to wild - type in hla b27 babies that had been infected by b27 mothers carrying the mutated virus . this was directly tested in vitro by schneidewind et al . , who showed that an infectivity fitness cost for the r264k mutation was compensated for by the a173s mutation ( 4 ) . this requirement for a triple mutation must be much rarer than a single mutation , and probably accounts for the delayed escape from this t cell response . diagrammatic representation of the side chains of the hiv-1 gag peptide krwiilglnk bound to hla - b27 , according to the structure determined by stewart - jones et al . the floor of the peptide - binding groove below the peptide and  2 helix are not depicted . only the side chains of leucine 268 ( l6 ) and asparagine 271 ( n9 ) are exposed to the t cell receptor . in this issue , lichterfeld et al . ( 11 ) report a longitudinal study , which shows that the l268 m change occurs early in infection , suggesting that it is the first in the sequence of changes that leads to escape , and that the mutation becomes fixed ( table i ) . fixation implies that the mutation confers some advantage for the virus in the presence of the t cell response . the leucine at this position is likely to interact with the t cell receptor ( fig . 1 ) , and the initial t cell response tends to be specific for the l - containing epitope . this response then drives selection of the m - containing mutant , which in turn stimulates a new cross - reactive t cell response ( 11 ) . any advantage of the m - containing epitope would therefore seem to be transient , but the fact that this mutation persists suggests that it confers some other , as yet unknown , advantage to the virus . lichterfeld et al . now give an intriguing insight into what this advantage might be . they show that complexes of the l268 m mutant peptide bound to hla b27 bind to ilt4 with three times higher affinity than do complexes of the wild - type peptide with hla b27 . ilt4 is present on monocytes and dcs , and contains a cytoplasmic itim motif that delivers an inhibitory signal to the cell . the authors show , however , that after the l268 m mutation occurs , a vigorous new primary t cell response develops against the new epitope . this fact is difficult to square with impaired dc function , but the authors provide a potential explanation . they show that ilt4 expression on monocytes and dcs is low in early hiv infection and increases as the infection progresses . they argue that if the l268 m mutation arises early in the infection , the dcs can still prime new t cell responses , but as the infection progresses and ilt4 expression increases , other new t cell responses may be impaired by the ilt4-mediated inhibition of dcs . it will thus be interesting to compare the breadth of t cell responses late in infection in b27 patients who do or do not have this epitope mutation . this is the first demonstration that mutation in an hiv-1 ctl epitope can contribute to virus escape by influencing the interaction between hla class i and a molecule other than the t cell receptor , although it is known that different epitope peptides ( none yet known to escape ) can influence the interaction between hla molecules and other inhibitory receptors , such as the kir family ( 12 ) . the virus must be under considerable immune pressure to select this complex mosaic of mutations ( table i ) . yet ultimately the virus evades immune control with the triple mutation and the virus load rises ( 8) . because this requires such a long period of time , other factors such as the loss of cd4 t cells must also contribute to the progression to aids . however , patients with b27 do progress to disease more slowly than the average hiv - infected individual , possibly because the b27-restricted t cells concentrate on a conserved part of the virus that requires this complicated and slow evasion process .
human immunodeficiency virus ( hiv ) type 1 is highly efficient at evading immune responses and persisting , ultimately causing fatal immunodeficiency in some patients . 
 mutation in the epitopes recognized by cytolytic cd8 + t cells ( ctls ) is one such escape process . 
 a new study now shows that one hiv-1 escape mutation may also result in impaired dendritic cell ( dc ) activity , possibly impairing later t cell responses to the same and other epitopes . 
 the new data complete our understanding of the mechanisms by which the ctl response to an immunodominant gag epitope presented by human histocompatibility leukocyte antigen ( hla)-b27 is evaded . 
 the complexity of the full escape helps to explain why patients with this hla type progress to aids more slowly than average .