Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy

Abstract

Background: Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.

Methods: We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.

Results: Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039).

Conclusion: HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

Figure 1

T cell activation among HIV-uninfected and HIV-infected participants by treatment status and level of viremia. The percentages of activated (CD38⁺HLA-DR⁺) CD4⁺ T cells (dark gray boxes) and CD8⁺ T cells (light gray boxes) are plotted among 47 HIV-uninfected participants, 30 controllers, 187 antiretroviral therapy (ART)–treated HIV-infected participants with plasma HIV RNA levels <75 copies/mL (VL<75), and 66 untreated HIV-infected participants with plasma HIV RNA levels >75 copies/mL (VL>75). The boxes span the 25th and 75th percentile values, the error bars span the 10th and 90th percentile values, each midline represents the median, and the dots represent individual observations below the 10th and above the 90th percentile values. Although controllers had lower CD4⁺ and CD8⁺ T cell activation levels than untreated HIV-infected participants with detectable viremia (P < .001, for both), they had higher CD4⁺ and CD8⁺ T cell activation levels than uninfected participants (P < .001, for both) and higher CD8⁺ T cell activation levels than treated participants with undetectable plasma HIV RNA levels (P = .048).

Figure 2

CD4⁺ T cell count by T cell activation level among 30 untreated HIV-infected patients with plasma HIV RNA levels <75 copies/mL. CD4⁺ T cell counts are plotted against the percentage of activated (CD38⁺HLA-DR⁺) CD4⁺ (A) and CD8⁺ (B) T cells. Each black line represents the unadjusted linear regression estimate. Among controllers, each 2-fold increase in the percentage of activated CD4⁺ T cells was associated with a mean of 165 fewer CD4⁺ T cells/mm³ (P = .016). Similarly, each 10% increase in activated CD8⁺ T cells was associated with a mean of 101 fewer CD4⁺ T cells/mm³ (P = .010).

Figure 3

Relationship between plasma lipopolysaccharide (LPS) level, plasma HIV RNA level, and CD8⁺ T cell activation. A, Plasma LPS levels compared between 31 HIV-uninfected participants, 14 HIV-infected controllers with undetectable viremia (plasma HIV RNA level <75 copies/mL [VL<75]), and 42 untreated HIV-infected patients with detectable viremia (plasma HIV RNA level >75 copies/mL [VL>75]). Elite controllers had higher LPS levels than HIV-uninfected participants (P < .001) but similar LPS levels compared with untreated HIV-infected participants with detectable viremia (P = .80). B, Percentage of activated (CD38⁺HLA-DR⁺) CD8⁺ T cells plotted by LPS level among 14 untreated controllers. Among controllers, higher LPS levels were associated with CD8⁺ T cell activation levels (Spearman's ρ = 0.56; P = .039).