Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus-Coinfected Women

Abstract

Background: Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus .

Methods: We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10.

Results: Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, -6.6% [P = .002]; CD4 T cells, -2.7% [P = .007]), C*18:01 (CD8 T cells, -6.6%; P < .0008) and DRB1*13:01 (CD4 T cells, -2.7%; P < .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P < .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03.

Conclusion: These findings suggest that a person's HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.

Keywords: HCV; HIV; HLA; T-cell activation; immune activation.

Figure 1.

Relationship between significant HLA alleles and CD8 (A) or CD4 (B) activation. Significant (P ≤ .05) associations of HLA alleles with percentage of CD8⁺CD38⁺DR⁺ (A) and log percentage of CD4⁺CD38⁺DR⁺ (B) T cells in multivariate linear models, with adjustments for race/ethnicity, principal components, age, laboratory data source, antiretroviral therapy, human immunodeficiency virus load, and hepatitis C virus status. The β estimate (with 95% confidence interval) is shown for each allele. *P ≤ .01 after adjustment for multiple tests (false discovery rate, <0.10).

Figure 2.

Violin plots showing percentages of CD8 and CD4 T-cell activation for each patient by HLA allele. Distributions of percentages of CD8⁺CD38⁺DR⁺ and CD4⁺CD38⁺DR⁺ T cells are shown by allele variant group. For plots of the allele variants, each point represents a unique subject. Activation levels at multiple visits were averaged for each subject. The “Other” group includes subjects with none of the allele variants.