Immune activation in HIV-infected aging women on antiretrovirals--implications for age-associated comorbidities: a cross-sectional pilot study

Abstract

Background: Persistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages.

Methods: Twenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163), microbial translocation (LPS) and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10) were evaluated.

Results: T cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation.

Conclusions: HIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls.

Figure 1. Elevated levels of microbial products in the bloodstream of HIV+ post-menopausal women are associated with the extent of immune activation.

Plasma levels of LPS were measured by the use of the Limulus amebocyte lysate chromogenic endpoint assay. Expression of activation (CD38, HLA-DR) and exhaustion (PD-1) markers was evaluated by flow cytometry in live CD4 and CD8 T cells. Circulating levels of sCD14 and sCD163 were measured by ELISA. (A–D) Graphs show the correlation between plasma LPS levels and: frequency of activated (A) and exhausted (B) CD8 T cells, and of activated (C) and exhausted (D) CD4 T cells. Correlations were established for 11 HIV– and 22 HIV+ women (continuous lines), and for the HIV+ women alone (dashed lines). (E, F) Graphs depict the correlation between plasma levels of LPS and those of sCD14 (E) or sCD163 (F) of 42 women (15 HIV–, open dots, and 27 HIV+, filled dots). Correlation between the two variables is indicated by the continuous line. Dashed line shows the correlation between the two variables when only the HIV+ subjects were taken into account. Significant P values are shown in bold.

Figure 2. Association between CD4 count, IA and MT in HIV+ post-menopausal women.

Markers of T cell activation (CD38, HLA-DR), exhaustion (PD-1) and senescence (loss of CD127 and CD28, CD57 expression) were established in live CD8 and CD4 T cells by multicolor flow cytometry. Circulating levels of sCD14 and sCD163 were measured by ELISA. Plasma LPS levels were measured by the Limulus amebocyte lysate chromogenic endpoint assay. (A–E) Graphs show correlation between CD4 T cell count and markers of T cell activation (A, B), exhaustion (C) and senescence (D, E) for 22 HIV+ donors. (F) Correlation between CD4 count and monocyte/macrophage activation markers sCD14 and sCD163 for 27 HIV+ women. (G) Correlation between CD4 count and plasma levels of LPS for 27 HIV+ women. Significant P values are shown in bold.

Figure 3. Biomarkers of CVD and cognitive impairment correlate with the status of immune activation and CD4 T cell count.

Correlation between the circulating levels of sVCAM-1, sICAM-1 and CXCL10 and those of plasma sCD25 (A), sCD14 (B), TNFα (C) and CD4 cell count (D). In each graph, the continuous line indicates the correlation between the two variables for all donors (HIV– and HIV+), while the dashed line shows the correlation between the two variables when only the HIV+ donors were taken into account. P values <0.05 are shown in bold.