Limits...
Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads.

Rolland M, Heckerman D, Deng W, Rousseau CM, Coovadia H, Bishop K, Goulder PJ, Walker BD, Brander C, Mullins JI - PLoS ONE (2008)

Bottom Line: In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire.Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads.The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA.

ABSTRACT

Background: HLA class-I alleles differ in their ability to control HIV replication through cell-mediated immune responses. No consistent associations have been found between the breadth of Cytotoxic T Lymphocytes (CTL) responses and the control of HIV-1, and it is unknown whether the size or distribution of the viral proteome-wide epitope repertoire, i.e., the intrinsic ability to present fewer, more or specific viral epitopes, could affect clinical markers of disease progression.

Methodology/principal findings: We used an epitope prediction model to identify all epitope motifs in a set of 302 HIV-1 full-length proteomes according to each individual's HLA (Human Leukocyte Antigen) genotype. The epitope repertoire, i.e., the number of predicted epitopes per HIV-1 proteome, varied considerably between HLA alleles and thus among individual proteomes. In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire. Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads.

Conclusions/significance: This comprehensive analysis puts forth the epitope repertoire as a mechanistic component of the multi-faceted HIV-specific CTL response. The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag.

Show MeSH

Related in: MedlinePlus

HIV-1 epitope repertoires and clinical data.Putative epitopes were identified in silico within full-length autologous HIV-1 proteomes and combined with previously described optimally defined CTL epitopes found in the LANL and IEDB databases. (A) and (B) respectively show the log viral loads and the CD4 counts plotted as a function of the number of predicted HIV-1 epitopes identified per proteome for the individuals with CD4 counts above 400 (n = 81). (C) Shows the number of predicted HIV-1 epitopes for individuals belonging to the highest (mean = 65) and lowest (mean = 76) viremia quartile. (D) Shows the average viral loads of individuals presenting a specific allele as a function of the average number of HIV-1 predicted epitopes for that allele (only alleles presented by at least 3 individuals in the South-African cohort were included).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2170517&req=5

pone-0001424-g001: HIV-1 epitope repertoires and clinical data.Putative epitopes were identified in silico within full-length autologous HIV-1 proteomes and combined with previously described optimally defined CTL epitopes found in the LANL and IEDB databases. (A) and (B) respectively show the log viral loads and the CD4 counts plotted as a function of the number of predicted HIV-1 epitopes identified per proteome for the individuals with CD4 counts above 400 (n = 81). (C) Shows the number of predicted HIV-1 epitopes for individuals belonging to the highest (mean = 65) and lowest (mean = 76) viremia quartile. (D) Shows the average viral loads of individuals presenting a specific allele as a function of the average number of HIV-1 predicted epitopes for that allele (only alleles presented by at least 3 individuals in the South-African cohort were included).

Mentions: We compared numbers of predicted epitopes per proteome to viral loads and CD4 counts in subtype C infected individuals from the South African cohort. We found that the more epitopes predicted for an individual, the lower the observed viral load (r2 = 0.0446, p = 0.0005; Spearman's correlation factor: Rho = −0.1751, p = 0.0039). In particular, we found a stronger negative relationship between the size of the epitope repertoire and the viral loads among the 81 individuals who had CD4 counts above 400, i.e., when we excluded from the analysis the individuals with vanishing T cell numbers, and presumably function (r2 = 0.1009, p = 0.0038; Spearman's correlation factor: Rho = −0.3090, p = 0.0050) (Figure 1A). Additionally, larger epitope repertoires were associated with higher CD4 counts (r2 = 0.0620, p = 0.0250; Spearman's Rho = 0.1549, p = 0.0395) (Figure 1B). A relatively weaker association was observed for CD4 than for viral loads, possibly due to CD4 counts being available for only 177 of the 270 individuals evaluated.


Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads.

Rolland M, Heckerman D, Deng W, Rousseau CM, Coovadia H, Bishop K, Goulder PJ, Walker BD, Brander C, Mullins JI - PLoS ONE (2008)

HIV-1 epitope repertoires and clinical data.Putative epitopes were identified in silico within full-length autologous HIV-1 proteomes and combined with previously described optimally defined CTL epitopes found in the LANL and IEDB databases. (A) and (B) respectively show the log viral loads and the CD4 counts plotted as a function of the number of predicted HIV-1 epitopes identified per proteome for the individuals with CD4 counts above 400 (n = 81). (C) Shows the number of predicted HIV-1 epitopes for individuals belonging to the highest (mean = 65) and lowest (mean = 76) viremia quartile. (D) Shows the average viral loads of individuals presenting a specific allele as a function of the average number of HIV-1 predicted epitopes for that allele (only alleles presented by at least 3 individuals in the South-African cohort were included).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2170517&req=5

pone-0001424-g001: HIV-1 epitope repertoires and clinical data.Putative epitopes were identified in silico within full-length autologous HIV-1 proteomes and combined with previously described optimally defined CTL epitopes found in the LANL and IEDB databases. (A) and (B) respectively show the log viral loads and the CD4 counts plotted as a function of the number of predicted HIV-1 epitopes identified per proteome for the individuals with CD4 counts above 400 (n = 81). (C) Shows the number of predicted HIV-1 epitopes for individuals belonging to the highest (mean = 65) and lowest (mean = 76) viremia quartile. (D) Shows the average viral loads of individuals presenting a specific allele as a function of the average number of HIV-1 predicted epitopes for that allele (only alleles presented by at least 3 individuals in the South-African cohort were included).
Mentions: We compared numbers of predicted epitopes per proteome to viral loads and CD4 counts in subtype C infected individuals from the South African cohort. We found that the more epitopes predicted for an individual, the lower the observed viral load (r2 = 0.0446, p = 0.0005; Spearman's correlation factor: Rho = −0.1751, p = 0.0039). In particular, we found a stronger negative relationship between the size of the epitope repertoire and the viral loads among the 81 individuals who had CD4 counts above 400, i.e., when we excluded from the analysis the individuals with vanishing T cell numbers, and presumably function (r2 = 0.1009, p = 0.0038; Spearman's correlation factor: Rho = −0.3090, p = 0.0050) (Figure 1A). Additionally, larger epitope repertoires were associated with higher CD4 counts (r2 = 0.0620, p = 0.0250; Spearman's Rho = 0.1549, p = 0.0395) (Figure 1B). A relatively weaker association was observed for CD4 than for viral loads, possibly due to CD4 counts being available for only 177 of the 270 individuals evaluated.

Bottom Line: In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire.Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads.The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA.

ABSTRACT

Background: HLA class-I alleles differ in their ability to control HIV replication through cell-mediated immune responses. No consistent associations have been found between the breadth of Cytotoxic T Lymphocytes (CTL) responses and the control of HIV-1, and it is unknown whether the size or distribution of the viral proteome-wide epitope repertoire, i.e., the intrinsic ability to present fewer, more or specific viral epitopes, could affect clinical markers of disease progression.

Methodology/principal findings: We used an epitope prediction model to identify all epitope motifs in a set of 302 HIV-1 full-length proteomes according to each individual's HLA (Human Leukocyte Antigen) genotype. The epitope repertoire, i.e., the number of predicted epitopes per HIV-1 proteome, varied considerably between HLA alleles and thus among individual proteomes. In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire. Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads.

Conclusions/significance: This comprehensive analysis puts forth the epitope repertoire as a mechanistic component of the multi-faceted HIV-specific CTL response. The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag.

Show MeSH
Related in: MedlinePlus