CYTOTOXIC T-CELL ACTIVITY ANTAGONIZED BY NATURALLY-OCCURRING HIV-1 GAG VARIANTS

MOST asymptomatic individuals infected with HIV-1 have a cytotoxic T l ymphocyte (CTL) response to the virus Gag proteins which can be demons trated in vitro(1,2). Epitopes have been mapped in p17 Gag and p24 Gag restricted by HLA-B8 (p17-3 and p24-13) and -B27 (p24-14)(2,3). Virus es isolated from patients who make CTL responses to these peptides var y within the genetic sequences encoding these epitopes and some mutati ons lead to reduction in killing activity in vitro(4). This mas attrib uted to either failure of the variant epitope to bind major histocompa tibility complex class I or failure of T-cell receptors to bind the pr esented peptide. But peptide variants of class I-restricted epitopes c ause 'antagonism', that is, the presence of a variant epitope (in the form of peptide) inhibits normal lysis of targets presenting the origi nal epitope(5,6). This mirrors similar findings in class II-restricted systems(7-10). Here we report that naturally occurring variant forms of p17-3, p24-13 and p24-14 may cause antagonism of CTL lines derived from the same individuals. The effect is present if the epitopes are d erived from synthetic peptides and when they are processed from full-l ength proteins expressed by either recombinant vaccinia constructs or replicating HIV.