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Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.

Migueles SA, Rood JE, Berkley AM, Guo T, Mendoza D, Patamawenu A, Hallahan CW, Cogliano NA, Frahm N, Duerr A, McElrath MJ, Connors M - PLoS Pathog. (2011)

Bottom Line: Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP.The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays.These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.

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HIV-specific CD8+ T-cell cytotoxic responses induced by an Ad5/HIV vaccine were similar to those of progressors.(A, B) Summary data of the total cytotoxic response measured by GrB activity (circles, A) or infected CD4+ T-cell elimination (ICE) (diamonds, B) with day 6 (D#6) CD8+ T-cells derived from LTNP (red symbols, n = 7), progressors (blue symbols, n = 10), HIV-negative individuals (black symbols, n = 10) and Ad5/HIV vaccinees (green symbols, n = 31). Data are representative of at least two experiments. Comparisons were made using the Wilcoxon two-sample test. Horizontal lines indicate median values. Only P values referring to comparisons between the responses of vaccinees and the other groups are shown. (C) Using D#6 CD8+ T-cells, GrB target cell activity correlates directly with ICE (n = 58). Correlation was determined by the Spearman rank method.
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ppat-1002002-g001: HIV-specific CD8+ T-cell cytotoxic responses induced by an Ad5/HIV vaccine were similar to those of progressors.(A, B) Summary data of the total cytotoxic response measured by GrB activity (circles, A) or infected CD4+ T-cell elimination (ICE) (diamonds, B) with day 6 (D#6) CD8+ T-cells derived from LTNP (red symbols, n = 7), progressors (blue symbols, n = 10), HIV-negative individuals (black symbols, n = 10) and Ad5/HIV vaccinees (green symbols, n = 31). Data are representative of at least two experiments. Comparisons were made using the Wilcoxon two-sample test. Horizontal lines indicate median values. Only P values referring to comparisons between the responses of vaccinees and the other groups are shown. (C) Using D#6 CD8+ T-cells, GrB target cell activity correlates directly with ICE (n = 58). Correlation was determined by the Spearman rank method.

Mentions: We have previously observed large differences in cytotoxic capacity between LTNP and viremic or ART-suppressed progressors, however, these measurements have not been applied to vaccinees. In their current form, these assays require large numbers of PBMC. For this reason, cells from participants in two trials (HVTN 071 and 502) in which vaccinees were leukapheresed or gave large blood volumes after either 2 or 3 doses, respectively, of the Merck Ad5/HIV trivalent vaccine were used. We have observed in prior work that although some differences in the cytotoxic capacity of unstimulated HIV-specific CD8+ T-cells were detectable between groups of chronically infected patients, the differences were largest in a recall response after a 6-day incubation with infected CD4+ T-cells [8], [19]. This likely represents the time necessary for upregulation of perforin under conditions of low levels of antigen such as would be expected in both LTNP and vaccinees. HIV-specific CD8+ T-cell cytotoxic responses measured by granzyme (Gr) B target cell activity and infected CD4+ T-cell elimination (ICE) were readily detectable in vaccine recipients (Table S1, Figure S1, Figure 1). The recall cytotoxic responses mediated by the cells of vaccinees (median GrB activity 15.6%, range 3-37.7%; median ICE 32.6%, range 5.8-61.5%) were significantly higher than those observed in HIV-negative controls (median GrB activity 1.7%, range 0-7.46%, p<0.001; median ICE 0.29%, range 0-3.3%, p<0.001; Figure 1A, B). In comparisons with chronically HIV-infected patients (Table S2), cytotoxic responses of vaccinees were significantly lower than, and completely non-overlapping with, those of LTNP (median GrB activity 50.7%, range 42.9-63%, p<0.001; median ICE 82.5%, range 75.2-86.6%, p<0.001; Figure 1A, B). Their responses were, however, comparable to those of progressors (median GrB activity 16.55%, range 3.03-39%, p>0.5; median ICE 37.35%, range 3.9-56%, p>0.5; Figure 1A, B). HIV-specific CD8+ T-cell cytotoxic responses measured by GrB or ICE were strongly, directly correlated with each other (R = 0.92, p<0.001), as observed previously in chronically infected patients (Figure 1C) [8], [19].


Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.

Migueles SA, Rood JE, Berkley AM, Guo T, Mendoza D, Patamawenu A, Hallahan CW, Cogliano NA, Frahm N, Duerr A, McElrath MJ, Connors M - PLoS Pathog. (2011)

HIV-specific CD8+ T-cell cytotoxic responses induced by an Ad5/HIV vaccine were similar to those of progressors.(A, B) Summary data of the total cytotoxic response measured by GrB activity (circles, A) or infected CD4+ T-cell elimination (ICE) (diamonds, B) with day 6 (D#6) CD8+ T-cells derived from LTNP (red symbols, n = 7), progressors (blue symbols, n = 10), HIV-negative individuals (black symbols, n = 10) and Ad5/HIV vaccinees (green symbols, n = 31). Data are representative of at least two experiments. Comparisons were made using the Wilcoxon two-sample test. Horizontal lines indicate median values. Only P values referring to comparisons between the responses of vaccinees and the other groups are shown. (C) Using D#6 CD8+ T-cells, GrB target cell activity correlates directly with ICE (n = 58). Correlation was determined by the Spearman rank method.
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getmorefigures.php?uid=PMC3044701&req=5

ppat-1002002-g001: HIV-specific CD8+ T-cell cytotoxic responses induced by an Ad5/HIV vaccine were similar to those of progressors.(A, B) Summary data of the total cytotoxic response measured by GrB activity (circles, A) or infected CD4+ T-cell elimination (ICE) (diamonds, B) with day 6 (D#6) CD8+ T-cells derived from LTNP (red symbols, n = 7), progressors (blue symbols, n = 10), HIV-negative individuals (black symbols, n = 10) and Ad5/HIV vaccinees (green symbols, n = 31). Data are representative of at least two experiments. Comparisons were made using the Wilcoxon two-sample test. Horizontal lines indicate median values. Only P values referring to comparisons between the responses of vaccinees and the other groups are shown. (C) Using D#6 CD8+ T-cells, GrB target cell activity correlates directly with ICE (n = 58). Correlation was determined by the Spearman rank method.
Mentions: We have previously observed large differences in cytotoxic capacity between LTNP and viremic or ART-suppressed progressors, however, these measurements have not been applied to vaccinees. In their current form, these assays require large numbers of PBMC. For this reason, cells from participants in two trials (HVTN 071 and 502) in which vaccinees were leukapheresed or gave large blood volumes after either 2 or 3 doses, respectively, of the Merck Ad5/HIV trivalent vaccine were used. We have observed in prior work that although some differences in the cytotoxic capacity of unstimulated HIV-specific CD8+ T-cells were detectable between groups of chronically infected patients, the differences were largest in a recall response after a 6-day incubation with infected CD4+ T-cells [8], [19]. This likely represents the time necessary for upregulation of perforin under conditions of low levels of antigen such as would be expected in both LTNP and vaccinees. HIV-specific CD8+ T-cell cytotoxic responses measured by granzyme (Gr) B target cell activity and infected CD4+ T-cell elimination (ICE) were readily detectable in vaccine recipients (Table S1, Figure S1, Figure 1). The recall cytotoxic responses mediated by the cells of vaccinees (median GrB activity 15.6%, range 3-37.7%; median ICE 32.6%, range 5.8-61.5%) were significantly higher than those observed in HIV-negative controls (median GrB activity 1.7%, range 0-7.46%, p<0.001; median ICE 0.29%, range 0-3.3%, p<0.001; Figure 1A, B). In comparisons with chronically HIV-infected patients (Table S2), cytotoxic responses of vaccinees were significantly lower than, and completely non-overlapping with, those of LTNP (median GrB activity 50.7%, range 42.9-63%, p<0.001; median ICE 82.5%, range 75.2-86.6%, p<0.001; Figure 1A, B). Their responses were, however, comparable to those of progressors (median GrB activity 16.55%, range 3.03-39%, p>0.5; median ICE 37.35%, range 3.9-56%, p>0.5; Figure 1A, B). HIV-specific CD8+ T-cell cytotoxic responses measured by GrB or ICE were strongly, directly correlated with each other (R = 0.92, p<0.001), as observed previously in chronically infected patients (Figure 1C) [8], [19].

Bottom Line: Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP.The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays.These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.

Show MeSH
Related in: MedlinePlus