CD4+ T cell targeting of human immunodeficiency virus type 1 (HIV-1) peptide sequences present in vivo during chronic, progressive HIV-1 disease

Abstract

We previously detected HIV-1 Gag-specific CD4+ T cells recognizing reference strain viral epitopes in subjects with progressive, chronic infection. To test whether these CD4+ T cells persist in vivo by failing to recognize autologous HIV-1 epitopes, we compared autologous plasma HIV-1 p24 nucleotide sequences with targeted HXB.2 strain Gag p24 CD4+ T cell epitopes in nine chronically infected, untreated subjects. In five responding subjects, 10 of 26 HXB.2 strain p24 peptides targeted by CD4+ T cells exactly matched autologous plasma viral sequences. Four subjects with plasma viral loads >100,000 copies/mL had no measurable p24-specific CD4+ T cell responses despite carrying HIV-1 strains that matched HXB.2 sequences at predicted epitopes. These results show that HIV-1-specific CD4+ T cells can persist in chronic HIV-1 infection despite recognition of epitopes present in vivo. However, with high-level in vivo HIV-1 replication, CD4+ T cells targeting autologous HIV-1 may be non-responsive or absent.

Figure 1

Significant inverse correlation of plasma HIV-1 RNA level with number of p24-specific CD4⁺ T cell target peptides, as shown for each study subject in Table II. Spearman R and p values are shown.

Figure 2

Neighbor-joining phylogenetic tree showing clustering of plasma HIV-1 Gag p24 molecular clones at the nucleotide level. Each terminal branch represents a single molecular clone; clusters of clones from each subject are labeled with subject numbers. Numbers at nodes indicate percentages of 1,000 bootstrap resamplings in which given clusters were supported. Distances between clones are determined by summation of intervening horizontal branch lengths. The scale bar represents a distance of 1.0% nucleotide non-identity between sequences. HXB.2 is the clade B reference strain upon which synthetic peptides were based. The sequence of AY334290, an HIV-1 clade A isolate derived in Ethiopia, was obtained from the Los Alamos HIV Sequence Database and included to show proximity to the sequences from UH156, who was infected with HIV-1 in Ethiopia.