Limits...
HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

Erdmann N, Du VY, Carlson J, Schaefer M, Jureka A, Sterrett S, Yue L, Dilernia D, Lakhi S, Tang J, Sidney J, Gilmour J, Allen S, Hunter E, Heath S, Bansal A, Goepfert PA - PLoS Pathog. (2015)

Bottom Line: However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001).CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus.These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT
Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP) in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE) or its non-adapted (NAE) version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001). However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001). CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

No MeSH data available.


Related in: MedlinePlus

CD4+ T cell adapted epitopes (AE) are poorly immunogenic during acute infection.(A) Median number of NAE and AE encoded by transmitted founder virus (TFV) that infected each of the 11 acute patients is indicated. Error bars represent the interquartile range of the median. (B) For each unique HLA-II predicted epitope, relevant NAE or AE peptide matching the determined TFV sequence was tested in IFN-γ ELISpot. Percentage of NAE or AE that was immunogenic in at least one patient is shown. Fractions represent number of epitopes that elicited a response / total number of epitopes tested. Fisher’s exact test was used to determine significance.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4547780&req=5

ppat.1005111.g003: CD4+ T cell adapted epitopes (AE) are poorly immunogenic during acute infection.(A) Median number of NAE and AE encoded by transmitted founder virus (TFV) that infected each of the 11 acute patients is indicated. Error bars represent the interquartile range of the median. (B) For each unique HLA-II predicted epitope, relevant NAE or AE peptide matching the determined TFV sequence was tested in IFN-γ ELISpot. Percentage of NAE or AE that was immunogenic in at least one patient is shown. Fractions represent number of epitopes that elicited a response / total number of epitopes tested. Fisher’s exact test was used to determine significance.

Mentions: A limitation to studies in chronically-infected HIV patients is that they harbor highly heterogeneous HIV-1 variants. Therefore, it is not possible to ascertain whether an immune response reflects a de novo response elicited by that epitope or cross presentation of an epitope variant. To accurately identify epitope-induced responses, we used single genome amplification technique [28–30] to obtain transmitted founder virus (TFV) sequences from the plasma of 11 clade B acutely infected patients (Fiebig stages I-III, S2 Table). Taking into consideration each donor’s HLA-II alleles, we determined the number of NAE and AE encoded by TFV that established infection in each acute patient (number of encoded NAE and AE for a representative patient is shown in S5 Table). While the number of transmitted NAE and AE varied from individual to individual (range of 2–10 for NAE, 2–7 for AE), the median numbers encoded by the TFV per infected individual were similar (Fig 3A), indicating that transmission of CD4+ AE variants is relatively common. Overall, in these 11 patients, we identified 52 and 53 predicted NAE and AE, respectively, encoded in the TFV. After stimulating each patient’s PBMC with the appropriate TFV-encoded epitopes (NAE or AE) in an IFN-γ ELISPOT assay, only 1/53 AE peptide elicited an immune response versus 9/52 NAE specific responses (p = 0.008) (Fig 3B). Each predicted polymorphism represents a possible CD4+ T-cell escape mutation, as AE are poorly immunogenic even when encoded by the TFV. The presence of AE in the TFV, therefore, possibly represents CD4+ T cell epitopes that have escaped in a prior host.


HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

Erdmann N, Du VY, Carlson J, Schaefer M, Jureka A, Sterrett S, Yue L, Dilernia D, Lakhi S, Tang J, Sidney J, Gilmour J, Allen S, Hunter E, Heath S, Bansal A, Goepfert PA - PLoS Pathog. (2015)

CD4+ T cell adapted epitopes (AE) are poorly immunogenic during acute infection.(A) Median number of NAE and AE encoded by transmitted founder virus (TFV) that infected each of the 11 acute patients is indicated. Error bars represent the interquartile range of the median. (B) For each unique HLA-II predicted epitope, relevant NAE or AE peptide matching the determined TFV sequence was tested in IFN-γ ELISpot. Percentage of NAE or AE that was immunogenic in at least one patient is shown. Fractions represent number of epitopes that elicited a response / total number of epitopes tested. Fisher’s exact test was used to determine significance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4547780&req=5

ppat.1005111.g003: CD4+ T cell adapted epitopes (AE) are poorly immunogenic during acute infection.(A) Median number of NAE and AE encoded by transmitted founder virus (TFV) that infected each of the 11 acute patients is indicated. Error bars represent the interquartile range of the median. (B) For each unique HLA-II predicted epitope, relevant NAE or AE peptide matching the determined TFV sequence was tested in IFN-γ ELISpot. Percentage of NAE or AE that was immunogenic in at least one patient is shown. Fractions represent number of epitopes that elicited a response / total number of epitopes tested. Fisher’s exact test was used to determine significance.
Mentions: A limitation to studies in chronically-infected HIV patients is that they harbor highly heterogeneous HIV-1 variants. Therefore, it is not possible to ascertain whether an immune response reflects a de novo response elicited by that epitope or cross presentation of an epitope variant. To accurately identify epitope-induced responses, we used single genome amplification technique [28–30] to obtain transmitted founder virus (TFV) sequences from the plasma of 11 clade B acutely infected patients (Fiebig stages I-III, S2 Table). Taking into consideration each donor’s HLA-II alleles, we determined the number of NAE and AE encoded by TFV that established infection in each acute patient (number of encoded NAE and AE for a representative patient is shown in S5 Table). While the number of transmitted NAE and AE varied from individual to individual (range of 2–10 for NAE, 2–7 for AE), the median numbers encoded by the TFV per infected individual were similar (Fig 3A), indicating that transmission of CD4+ AE variants is relatively common. Overall, in these 11 patients, we identified 52 and 53 predicted NAE and AE, respectively, encoded in the TFV. After stimulating each patient’s PBMC with the appropriate TFV-encoded epitopes (NAE or AE) in an IFN-γ ELISPOT assay, only 1/53 AE peptide elicited an immune response versus 9/52 NAE specific responses (p = 0.008) (Fig 3B). Each predicted polymorphism represents a possible CD4+ T-cell escape mutation, as AE are poorly immunogenic even when encoded by the TFV. The presence of AE in the TFV, therefore, possibly represents CD4+ T cell epitopes that have escaped in a prior host.

Bottom Line: However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001).CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus.These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT
Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP) in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE) or its non-adapted (NAE) version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001). However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001). CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

No MeSH data available.


Related in: MedlinePlus