Consistent Cytotoxic-T-Lymphocyte Targeting of Immunodominant Regions in Human Immunodeficiency Virus across Multiple Ethnicities

Abstract

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8؉ -T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8؉ -T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef-and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8؉ -T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

In vivoCD8+T cell control of immunodeficiency virus infection in humans and macaques

“…Indeed, in humans, protective alleles appear to be associated with decreased frequency of escape (22). There is no evidence that humans have broader CTL responses (i.e., recognize more epitopes) than macaques (24)(25)(26)(27)(28)(29), so, given the observation that individual CTL responses kill virus-infected cells more rapidly in macaques than in humans, we conclude that the total CTL response kills immunodeficiency virus-infected cells more rapidly in macaques than in humans. Our work does not enable us to determine whether CD8 ϩ T cells from macaques kill at a faster rate because there are more CD8 ϩ T cells targeting each peptide or because the per-CD8 ϩ T cell rate of killing is higher.…”

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…1A). Compared with other targets of the HLA-A2-restricted response, these data identify TV9 as an infrequently targeted epitope in natural HIV infection (61). Interestingly, the frequency and functional sensitivity of TV9-reactive cells were relatively high with a SD 50 value of ϳ0.0001 g/ml (54) in L8 47, indicating that the in vivo CD8 ϩ T cell response to this epitope can be highly avid despite its subdominance in natural infection.…”

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

“…The existence of this ORF and of the encoded protein was controversial for many years, but now several pieces of evidence argue in favor of its expression (see ref. 4 for an extensive review): (i) several polyadenylated antisense transcripts capable of encoding ASP have been characterized within HIV-1-infected cells (1,5,6); (ii) it was demonstrated that the full-length ASP protein can be expressed ex vivo from the HIV-1 3′ LTR (7); (iii) ASP has been detected in freshly infected cells (2,8,9); and (iv) two recent independent clinical studies have shown the in vivo expression of ASP by detecting a cell-mediated immune response against several ASP epitopes within 30% of individuals infected with subtype B viruses (10,11) [a percentage similar to those observed with other HIV-1 proteins, e.g., Tat and Pol (12)]. Moreover, experimental results suggested that ASP could form stable aggregates, be located partially at the plasma membrane, and be associated with autophagy (4,7,8).…”