High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort

Damalie Nakanjako, Isaac Ssewanyana, Harriet Mayanja-Kizza, Agnes Kiragga, Robert Colebunders, Yukari C Manabe, Rose Nabatanzi, Moses R Kamya, Huyen Cao, Damalie Nakanjako, Isaac Ssewanyana, Harriet Mayanja-Kizza, Agnes Kiragga, Robert Colebunders, Yukari C Manabe, Rose Nabatanzi, Moses R Kamya, Huyen Cao

Abstract

Background: Antiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated.

Methods: T-cell activation (CD38+HLA-DR+) and immune exhaustion (PD-1+) were measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: Suboptimal [median CD4 count increase 129 (-43-199) cells/μl], N = 34 ], optimal [282 (200-415) cells/μl, N = 64] and super-optimal [528 (416-878) cells/μl, N = 30].

Results: Both CD4+ and CD8 T-cell activation was significantly higher among suboptimal CD4 T-cell responders compared to super-optimal responders. In a multivariate model, CD4+CD38+HLADR+ T-cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4-23, P = 0.014)]. T-cell exhaustion (CD4+PD1+ and CD8+PD1+) was higher among suboptimal relative to optimal (P < 0.001) and super-optimal responders (P < 0.001). T-cell exhaustion was significantly associated with suboptimal responders [AOR, 1.5 (95%CI, 1.1-2.1), P = 0.022].

Conclusion: T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART.

Figures

Figure 1
Figure 1
Profile of patients on antiretroviral therapy within the Infectious Disease research cohort.
Figure 2
Figure 2
Flow cytometry analysis of CD38+HLADR+ CD8 T cells. The upper panel shows the gating strategy for co-expression of CD38 and HLADR (immune activation) by CD8 T cells. The lower panel shows a 'super responder' with a typically low proportion of activated CD8 T cells (left) and a 'suboptimal responder' with a typically high proportion of activated CD8 T cells.
Figure 3
Figure 3
T-cell activation and magnitude of CD4 count increase among HIV-infected patients after 4 years of antiretroviral therapy and sustained HIV-RNA viral suppression. Immune activation, was measured by co-expression of HLADR and CD38 (CD38+HLADR+). The percentages of activated CD4 (CD438+HLADR+) and CD8 (CD8 CD38+ HLADR+) T-cells were plotted against CD4 count reconstitution. Immune activation of CD4 and CD8 T-cells was higher among patients with suboptimal CD4 reconstitution (patients that lie in the lowest quartile of CD4 increase) relative to the super-optimal responders (patients that lie in the highest quartile of CD4 increase) P = 0.001. The boxes span the 25th and 75th percentile values, the error bars span the 10th and 90th percentile values, and the dots represent individual observations above the 90th percentile values.
Figure 4
Figure 4
Flow cytometry analysis of PD1+ CD4 T cells for an individual with suboptimal CD4 reconstitution. The upper panel shows the gating strategy for the PD1+ T cells that are marked for apoptosis. The lower panel shows the fluorescence minus one control (FMO) for PD1 (left) and a typically high proportion of PD1+ cells (right).
Figure 5
Figure 5
T-cell exhaustion among HIV-infected patients after 4 years of antiretroviral therapy with sustained HIV-RNA viral suppression. T-cell exhaustion was measured by expression of programmed cell death 1 (PD-1) by CD4 and CD8 cells (CD4 PD1+ and CD8 PD1+). The percentages of CD4 PD1+ and CD8 PD1+ T-cells were plotted against CD4 count reconstitution. Exhaustion of CD4 and CD8 T-cells was significantly higher among patients with suboptimal CD4 reconstitution (patients that lie within the lowest quartile of CD4 increase) relative to optimal responders (patients that lie within the middle quartiles of CD4 increase and super-optimal responders (patients that lie within the highest quartile of CD4 increase) P = 0.001. The boxes span the 25th and 75th percentile values, the error bars span the 10th and 90th percentile values, and the dots represent individual observations above the 90th percentile values.

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