T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women

Abstract

Background: Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults.

Methods: T cell phenotyping and carotid ultrasound were assessed among 115 HIV-infected women and 43 age- and race/ethnicity-matched HIV-uninfected controls participating in the Women's Interagency HIV Study. Multivariate analyses were used to assess the association of T cell activation (CD38(+)HLA-DR(+)) and senescence (CD28(-)CD57(+)) with subclinical carotid artery disease.

Results: Compared with HIV-uninfected women, frequencies of CD4(+)CD38(+)HLA-DR(+), CD8(+)CD38(+)HLA-DR(+), and CD8(+)CD28(-)CD57(+) T cells were higher among HIV-infected women, including those who achieved viral suppression while receiving antiretroviral treatment. Among HIV-infected women, adjusted for age, antiretroviral medications, and viral load, higher frequencies of activated CD4(+) and CD8(+) T cells and immunosenescent CD8(+) T cells were associated with increased prevalence of carotid artery lesions (prevalence ratio(lesions) associated with activated CD4(+) T cells, 1.6 per SD [95% confidence interval {CI}, 1.1-2.2]; P = .02; prevalence ratio(lesions) associated with activated CD8(+) T cells, 2.0 per SD [95% CI, 1.2-3.3]; P < .01; prevalence ratio(lesions) associated with senescent CD8(+) T cells, 1.9 per SD [95% CI, 1.1-3.1]; P = .01).

Conclusions: HIV-associated T cell changes are associated with subclinical carotid artery abnormalities, which may be observed even among those patients achieving viral suppression with effective antiretroviral therapy.

Figure 1.

Expression of activation (CD38 and HLA-DR) and senescence (CD57 and CD28) markers on CD4⁺ and CD8⁺ T cells. Representative fluorescence-activated cell-sorting plots showing gating of T cells to define CD4⁺ and CD8⁺ T cells (A), activation markers to define CD38⁺HLA-DR⁺ T cells (B), and senescent markers to define CD28⁻CD57⁺ T cells (C). Data were compensated and analyzed using FlowJo software (Treestar). Standard lymphocyte and singlet gates were drawn to exclude debris, monocytes, and doublets. Dead cells were excluded by gating on aqua amine reactive dye–negative cells, and total T cells were defined by CD3⁺ staining. Fluorescence-minus-1 controls were used to set T cell subpopulation gates. The mean peripheral blood mononuclear cell viability was 75.0% in human immunodeficiency virus (HIV)–infected women and 77.5% in HIV-uninfected women.

Figure 2.

T cell activation (CD38⁺HLA-DR⁺) and senescence (CD28⁻CD57⁺) among 115 human immunodeficiency virus (HIV)–infected women and 43 HIV-uninfected women. HIV-infected women include 41 who were not receiving antiretroviral therapy at the time of the study (Untreated), 29 who were receiving highly active antiretroviral therapy and had no detectable plasma HIV (Aviremic), and 45 who were treated and had detectable plasma HIV (Viremic). P < .01 (Kruskal-Wallis test) for CD4⁺ T cell activation, CD8⁺ T cell activation, and CD8⁺ T cell senescence in comparing the HIV-infected group with the HIV-uninfected group. For CD4⁺ T cell senescence, P = .07 in comparing the HIV-infected group with the HIV-uninfected group.

Figure 3.

T-cell activation (CD38⁺HLA-DR⁺) and senescence (CD28⁻CD57⁺) in relation to carotid lesions. Among human immunodeficiency virus (HIV)–infected women, higher CD4⁺CD38⁺HLA-DR⁺ T cell frequency (P = .02) and higher CD8⁺CD38⁺HLA-DR⁺ T cell frequency (P = .04) were observed among 19 women with carotid lesions than among 96 women without carotid lesions. Similarly, among HIV-infected women, CD8⁺CD28⁻CD57⁺ T cell frequency was higher among those with carotid lesions than among those without carotid lesions (P = .03). No significant difference in CD4⁺CD28⁻CD57⁺ T cell frequency was observed in comparing HIV-infected women with and without lesions. Among 43 HIV-uninfected women, none of these T cell parameters differed according to the presence or absence of carotid lesions. P values were computed using the Kruskal-Wallis test.