Vaccine-induced CD8+ T cells control AIDS virus replication

Abstract

Developing a vaccine for human immunodeficiency virus (HIV) may be aided by a complete understanding of those rare cases in which some HIV-infected individuals control replication of the virus. Most of these elite controllers express the histocompatibility alleles HLA-B*57 or HLA-B*27 (ref. 3). These alleles remain by far the most robust associations with low concentrations of plasma virus, yet the mechanism of control in these individuals is not entirely clear. Here we vaccinate Indian rhesus macaques that express Mamu-B*08, an animal model for HLA-B*27-mediated elite control, with three Mamu-B*08-restricted CD8(+) T-cell epitopes, and demonstrate that these vaccinated animals control replication of the highly pathogenic clonal simian immunodeficiency virus (SIV) mac239 virus. High frequencies of CD8(+) T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon were associated with viral control. Moreover, the frequency of the CD8(+) T-cell response against the Nef RL10 epitope (Nef amino acids 137-146) correlated significantly with reduced acute phase viraemia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8(+) T-cell responses in the control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8(+) T-cell responses can control replication of the AIDS virus.

Figure 1

Experimental design. A) Mamu-B*08⁺ macaques were vaccinated with an identical rYF17D/rAd5 regimen. Group 1 received two SIVmac239 constructs: Vif 3′ (amino acids 102–214; includes the Mamu-B*08-restricted Vif_123–131RL9 and Vif_172–179RL8 epitopes) and Nef (amino acids 45–210; includes the Mamu-B*08-restricted Nef_137–146RL10 epitope). Group 2 received two SIVmac239 constructs: Gag (amino acids 178–258) and Vif 5′ (amino acids 1–110), which do not contain any known Mamu-B*08-restricted CD8⁺ T cell epitopes. Animals were challenged with SIVmac239 intrarectally 15 weeks after the rAd5 boost. B) Frequencies of tetramer⁺ CD8⁺ T-cells in PBMC at days 7 and 14 following the rAd5 boost. Lines represent mean frequency.

Figure 2

In vivo viral replication. A) Plasma VLs for Group 1 animals. The dashed line (10³ vRNA copies/mL) represents the threshold that defines elite control in Indian rhesus macaques. B) Plasma VLs for Group 2 animals. C) Geometric mean plasma VLs for Groups 1, 2, and unvaccinated Mamu-B*08⁺ (n = 4) or Mamu-B*08⁻ (n = 8) control macaques. D) Plasma VL comparisons between Groups 1 and 2. Lines represent geometric means. E) Viral replication measured using in situ hybridization^, in lymph node biopsy specimens. The mean value and the standard error of the mean are shown.

Figure 3

CD8⁺ T-cell responses in vaccinated animals following SIVmac239 infection. Peptide/Mamu-B*08 tetramer staining in A) PBMC, B) lymph nodes, and C) colon biopsies. Error bars represent standard error of the mean. D) Correlations between the frequency of tetramer⁺ cells and VL at week 2 post infection. E) Granzyme B production by SIV-specific CD8⁺ T-cells in Group 1 and Group 2 vaccinees at days 7 and 17 post-infection. F) Perforin production by SIV-specific CD8⁺ T-cells in Group 1 and Group 2 vaccinees at day 17 post-infection. Assay results are shown as sport forming cells (SFC) per 10⁶ PBMC.