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1.
FIG. 5.

FIG. 5. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

Comparison of Mamu-B*08-restricted CD8+ T-cell responses detected by MHC class I tetramers during the first 18 weeks postinfection. Cryopreserved PBMC from the four Mamu-B*08-positive macaques (black, r91003; green, r01027; blue, r00032; and red, r02019) were thawed and stained at the indicated time points for the eight Mamu-B*08-restricted epitopes. Results of MHC class I tetramer stains are shown here as percentages of CD3+ CD8+ MHC class I tetramer-positive gated lymphocytes. The threshold of detection in these assays was 0.02% CD3+ CD8+ MHC class I tetramer-positive gated lymphocytes.

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.
2.
FIG. 7.

FIG. 7. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

Mutations in Mamu-B*08-restricted CD8+ T-cell epitopes occurred as early as 10 weeks postinfection. The ontogeny of substitutions in Vif123-131RL9, Vif172-179RL8, Nef137-146RL10, and Nef245-254RL9 was followed by sequencing of plasma virus between 4 and 18 weeks after SIVmac239 infection. The Nef137-146RL10 epitope is annotated with an asterisk to signify that the amino acid residue immediately N-terminal to the epitope, alanine (A), is also displayed. Viral variation at this position is associated with Mamu-B*08 expression (48). Amino acids identical to the wild-type sequence are shown as dots. Complete amino acid replacements are shown in uppercase; sites of mixed-base heterogeneity are shown in lowercase.

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.
3.
FIG. 6.

FIG. 6. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

Detection of CD4+ T-cell responses at 20 weeks postinfection by ex vivo CD8+ cell-depleted IFN-γ ELISPOT. Thirty-five peptide pools, with 10 15-mer peptides overlapping by 11 amino acids, spanning the entire SIVmac239 proteome (except for Pol and Env due to limited availability of PBMC) were tested in IFN-γ ELISPOT assays on PBMC depleted of CD8+ cells. Each column represents the number of SFC per 106 CD8+ cell-depleted PBMC directed against a single peptide pool at 20 weeks postinfection. Only positive responses are indicated. Background levels were subtracted from each well. Mean responses of <50 SFC per 1 × 106 cells (dashed line) were not considered positive.

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.
4.
FIG. 2.

FIG. 2. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

CD4+ memory T cells are maintained in Mamu-B*08-positive macaques infected with SIVmac239. (A) Absolute counts of CD4+ memory T cells were obtained from the four SIVmac239-infected, Mamu-B*08-positive macaques (blue lines) in addition to the four SIVmac239-infected, Mamu-B*08-negative macaques (red lines). Mamu-B*08-negative macaques r98059 and r00041 were infected along with the four Mamu-B*08-positive macaques. CD4+ memory T-cell counts from two additional Mamu-B*08-negative, -B*17-negative macaques (animals r95107 and r01035) were acquired from cryopreserved PBMC. Archived PBMC were not available at week 2 from r01035 or at week 18 from r01035 and r00041. In place of the week 18 time point, absolute counts of CD4+ memory T cells were acquired from the closest available time point (week 28), indicated in parentheses. (B) Geometric means of absolute counts of CD4+ memory T cells. The blue line represents the four Mamu-B*08-positive macaques, and the red line represents the four Mamu-B*08-negative macaques. By use of log-transformed arithmetic means, statistically significant differences were found between the absolute CD4+ memory T-cell counts of the Mamu-B*08-positive and -B*08-negative groups at the following time points: week 6 (P = 0.001), week 8 (P < 0.001), week 10 (P < 0.001), week 12 (P = 0.014), and week 18 (or 28) (P = 0.001).

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.
5.
FIG. 1.

FIG. 1. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

Three of four Mamu-B*08-positive Indian rhesus macaques control pathogenic SIVmac239 viral replication. Longitudinal SIVmac239 plasma virus concentrations were plotted for four Mamu-B*08-positive macaques (blue lines) and the geometric mean of viral loads from 10 Mamu-B*08-negative ECs and 175 Mamu-B*08-negative animals that progressed to AIDS (red lines) from a previous study (49). SIV-infected macaques r00032 (Mamu-A*02 positive and Mamu-B*08 positive) and r02019 (Mamu-B*08 positive) were considered ECs, with viral set points of ∼1 × 103 vRNA copies/ml. These two macaques had significantly lower viral set points (weeks 10 to 20 postinfection) than the macaques that progressed to AIDS (P = 0.0066 for r00032 and P = 0.0076 for r02019). Animal r01027 (Mamu-A*01 positive and Mamu-B*08 positive) is considered a “controller,” with viremia >1 log lower than typical SIV replication. The viral set point of r01027 was near statistical significance compared to those of the macaques that progressed to AIDS (P = 0.0578). None of these three macaques had P values significantly different from that for the viral set point of the EC cohort. One of the four macaques did not control SIVmac239 replication to <20,000 vRNA copies/ml after 10 weeks postinfection. Animal r91003 (Mamu-A*01 positive and Mamu-B*08 positive) exhibited typical viremia at ≥10 weeks postinfection that was not statistically different from that of the macaques that progressed to AIDS.

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.
6.
FIG. 4.

FIG. 4. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

Involvement of Mamu-B*08-restricted CD8+ T-cell responses in the overall CD8+ T-cell-mediated immune response against SIVmac239 at 3 weeks postinfection. (A) Mamu-B*08-restricted CD8+ T cells make a major contribution to the total SIV-specific immune response during the acute phase of infection. The contributions of known responses are shown for Mamu-A*01, Mamu-A*02, and Mamu-B*08 by attributing peptide pools to particular MHC class I molecules based on the locations of known SIV epitopes in these pools. (B) Mamu-B*08-restricted CD8+ T cells recognize a broader epitope repertoire in EC macaques early in SIV infection. CD8+ T-cell responses accounting for >10% of the total Mamu-B*08-restricted immune response are indicated above the appropriate bar. Minimal optimal peptides were used for the following Mamu-B*08-restricted epitopes: Vif123-131RL9, Vif172-179RL8, Rev44-51RL8, Env573-581KL9, and Nef246-254RL9. Mamu-B*08 epitopes annotated with an asterisk were represented with peptides slightly larger than the minimal optimal as these responses were in the process of being fine mapped (Rev12-20KL9* represents two overlapping 15-mer peptides positions 5 to 23, Nef8-16RL9* represents a 10-mer peptide at positions 7 to 16, and Nef137-146RL10* represents an 11-mer peptide at positions 136 to 146). Data for both panel A and panel B were derived from ex vivo IFN-γ ELISPOT assays at 3 weeks postinfection (Fig. 3). Background levels were subtracted from each well. Mean responses of <50 SFC per 1 × 106 cells (white bars) were not considered positive.

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.
7.
FIG. 3.

FIG. 3. From: Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication .

Ex vivo whole PBMC IFN-γ ELISPOT using peptides spanning the entire SIVmac239 proteome and the relevant MHC class I-restricted minimal optimal CD8+ T-cell epitopes at 3 weeks postinfection. Eighty-one peptide pools (10 15-mer peptides overlapping by 11 amino acids) were tested in IFN-γ ELISPOT assays spanning the complete SIVmac239 proteome. Total responses for each protein were calculated by adding the mean values of the individual peptide pools for each SIV protein. Individual minimal optimal peptides were included to detect responses restricted by Mamu-A*01 and Mamu-A*02. While the Mamu-A*01-restricted Gag181-189CM9 epitope was not tested (NT) in r91003, we can verify that a response to this epitope was detected at 3 weeks postinfection by the Gag161-211(E) peptide pool that contains the Gag181-189CM9 sequence (692 SFC/106 PBMC). MHC class I tetramer staining in r91003 confirms the presence of Gag181-189CM9-specific CD8+ T cells at this time point (see text). Two Mamu-A*02-restricted CD8+ T-cell epitopes are labeled as Nef YY9. Nef YY9 refers to the epitope at positions 159 to 167 (YTSGPGIRY), while Nef YY92 refers to the epitope at positions 221 to 229 (YTYEAYVRY). Minimal optimal peptides were used for the following Mamu-B*08-restricted epitopes: Vif123-131RL9, Vif172-179RL8, Rev44-51RL8, Env573-581KL9, and Nef246-254RL9. Mamu-B*08 epitopes annotated with an asterisk were represented with peptides slightly larger than the minimal optimal as these responses were in the process of being fine mapped (Rev12-20KL9* represents two overlapping 15-mer peptides at positions 5 to 23, Nef8-16RL9* represents a 10-mer peptide at positions 7 to 16, and Nef137-146RL10* represents an 11-mer peptide at positions 136 to 146). Background levels were subtracted from each well. Mean responses of <50 SFC per 1 × 106 cells (white bars) were not considered positive.

John T. Loffredo, et al. J Virol. 2008 February;82(4):1723-1738.

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