Limits...
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.

Show MeSH

Related in: MedlinePlus

HIV-specific CD8+ T-cell cytotoxic capacity in Ad5/HIV vaccine recipients was higher among individuals with protective HLA class I alleles.ICE responses mediated by day 6 CD8+ T-cells of vaccine recipients who possess the HLA class I alleles B*27, B*57 or B*58 that have been shown to be associated with nonprogressive HIV infection (n = 11) versus those of vaccine recipients not possessing these protective alleles (n = 20) was compared by the Wilcoxon two-sample test. Horizontal lines represent median values. Data are representative of at least two experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3044701&req=5

ppat-1002002-g005: HIV-specific CD8+ T-cell cytotoxic capacity in Ad5/HIV vaccine recipients was higher among individuals with protective HLA class I alleles.ICE responses mediated by day 6 CD8+ T-cells of vaccine recipients who possess the HLA class I alleles B*27, B*57 or B*58 that have been shown to be associated with nonprogressive HIV infection (n = 11) versus those of vaccine recipients not possessing these protective alleles (n = 20) was compared by the Wilcoxon two-sample test. Horizontal lines represent median values. Data are representative of at least two experiments.

Mentions: Given the preliminary data showing a trend towards an association between HLA haplotype and viral load in vaccinee cases of the Step trial (Nicole Frahm, personal communication), it was of interest to examine the cytotoxic capacity of vaccinees in the present study when stratified by HLA type. Interestingly, the cytotoxic responses of vaccine recipients carrying HLA class I alleles that have been associated with nonprogressive HIV infection, e.g., B*27, B*57 and B*58 (n = 11), were significantly greater than those of individuals not possessing these alleles (n = 20; median ICE 48.7% versus 25.4%, respectively, p = 0.001; Figure 5). Importantly, none of the individuals bearing these protective alleles exhibited a low response. These results suggest that, in contrast to patients not expressing protective alleles, vaccination in individuals carrying these alleles primes for greater HIV-specific CD8+ T-cell cytotoxic capacity.


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 capacity in Ad5/HIV vaccine recipients was higher among individuals with protective HLA class I alleles.ICE responses mediated by day 6 CD8+ T-cells of vaccine recipients who possess the HLA class I alleles B*27, B*57 or B*58 that have been shown to be associated with nonprogressive HIV infection (n = 11) versus those of vaccine recipients not possessing these protective alleles (n = 20) was compared by the Wilcoxon two-sample test. Horizontal lines represent median values. Data are representative of at least two experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044701&req=5

ppat-1002002-g005: HIV-specific CD8+ T-cell cytotoxic capacity in Ad5/HIV vaccine recipients was higher among individuals with protective HLA class I alleles.ICE responses mediated by day 6 CD8+ T-cells of vaccine recipients who possess the HLA class I alleles B*27, B*57 or B*58 that have been shown to be associated with nonprogressive HIV infection (n = 11) versus those of vaccine recipients not possessing these protective alleles (n = 20) was compared by the Wilcoxon two-sample test. Horizontal lines represent median values. Data are representative of at least two experiments.
Mentions: Given the preliminary data showing a trend towards an association between HLA haplotype and viral load in vaccinee cases of the Step trial (Nicole Frahm, personal communication), it was of interest to examine the cytotoxic capacity of vaccinees in the present study when stratified by HLA type. Interestingly, the cytotoxic responses of vaccine recipients carrying HLA class I alleles that have been associated with nonprogressive HIV infection, e.g., B*27, B*57 and B*58 (n = 11), were significantly greater than those of individuals not possessing these alleles (n = 20; median ICE 48.7% versus 25.4%, respectively, p = 0.001; Figure 5). Importantly, none of the individuals bearing these protective alleles exhibited a low response. These results suggest that, in contrast to patients not expressing protective alleles, vaccination in individuals carrying these alleles primes for greater HIV-specific CD8+ T-cell cytotoxic capacity.

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