Association of functional impairment with inflammation and immune activation in HIV type 1-infected adults receiving effective antiretroviral therapy

Abstract

Background: The relationships of inflammation, immune activation, and immunosenescence markers with functional impairment in aging human immunodeficiency virus type 1 (HIV-1)-infected persons are unknown.

Methods: HIV-infected persons who were aged 45-65 years, had a plasma HIV-1 RNA load of <48 copies/mL, and were receiving antiretroviral therapy underwent standardized functional testing. In a nested case-control analysis, low-functioning cases were matched (1:1-2) by age, sex, and HIV-1 diagnosis date to high-functioning controls. Markers of inflammation, T-cell activation, microbial translocation, immunosenescence, and immune recovery were used to estimate functional status in conditional logistic regression. Primary analyses were adjusted for CD4(+) T-cell count, smoking, and hepatitis.

Results: Thirty-one low-functioning cases were compared to 49 high-functioning controls. After statistical adjustment, lower proportions of CD4(+) T cells and higher proportion of CD8(+) T cells, higher CD38/HLA-DR expression on CD8(+) T cells, and higher interleukin-6 were associated with a significantly greater odds of low functional status (odds ratio, ≥ 1.1 for all analyses; P ≤ .03). Other inflammatory, senescence, and microbial translocation markers were not significantly different (P ≥ .11 for all analyses) between low-functioning and high-functioning groups.

Conclusions: Functional impairment during successful antiretroviral therapy was associated with higher CD8(+) T-cell activation and interleukin 6 levels. Interventions to decrease immune activation and inflammation should be evaluated for their effects on physical function and frailty.

Keywords: HIV; aging; frailty; functional capacity; functional impairment; functional status; immune activation; immunosenescence; inflammation; microbial translocation; physical function; senescence; telomeres.

Figure 1.

Comparison of T-lymphocyte subsets and immune activation (CD38 and HLA-DR expression on CD4⁺ and CD8⁺ T cells and soluble CD14 [sCD14] level) between low- and high-functioning groups. Means and standard errors are represented by bars and error bars, respectively. P values were determined by unadjusted comparison of means in a mixed-effects model to account for clustering from matched design.

Figure 2.

Comparison of inflammatory markers between low- and high-functioning persons. Comparisons for interleukin 6 (IL-6) and highly sensitive C-reactive protein (hs-CRP) are log transformed. Geometric means and 95% confidence intervals (for IL-6 and hs-CRP) or means and standard errors (for tumor necrosis factor α [TNF-α]) are represented by bars and error bars, respectively. P values were determined by unadjusted comparison of means in a mixed-effects model to account for clustering from matched design.

Figure 3.

Comparison of microbial translocation markers between low- and high-functioning persons. In panel A, the comparison for 16S ribosomal DNA (rDNA) is log transformed, and the dashed line represents the lower limit of detection. Means and standard errors, respectively, and geometric means and 95% confidence intervals (for 16S rDNA only), respectively, are represented by bars and error bars. P values were determined by unadjusted comparison of means in a mixed-effects model to account for clustering from matched design. Abbreviations: endoCAb, endotoxin core immunoglobulin M antibody; i-FABP, intestinal fatty acid–binding protein; LBP, lipopolysaccharide-binding protein; LPS, lipopolysaccharide; MU, median units of immunoglobulin M.

Figure 4.

Comparison of immunosenescence markers between low- and high-functioning persons. Means and standard errors are represented by bars and error bars, respectively. P values were determined by unadjusted comparison of means in a mixed-effects model to account for clustering from matched design.