Premature aging of T cells is associated with faster HIV-1 disease progression

Abstract

Objective: To determine if untreated HIV-1 infection and progression is associated with premature aging of memory CD8 and CD4 T cells and naive CD4 T cells.

Methods: Twenty HIV-1-infected fast progressors and 40 slow progressors were included in our study, using risk set sampling. The expression of cell surface markers reflecting the differentiation stages of lymphocytes was measured using flow cytometry analyses performed on cryopreserved peripheral blood mononuclear cells.

Results: We found that HIV-1 disease progression is associated with a decreased CD28 median florescence intensity on CD4 and CD8 T cells; an increased proportion of intermediate- and late-differentiated CD8 T cells and a decreased CD31 median florescence intensity on naive CD4 T cells of recent thymic origin. A selective depletion of peripherally expanded naive CD4 T cells was found to be associated with HIV-1 infection but not with HIV-1 disease progression.

Conclusions: The overall change during HIV-1 infection and progression is associated with a shift in the T-cell population toward an aged conformation, which may be further compromised by impaired renewal of the less-differentiated CD4 T-cell population. Our results suggest that HIV-1 infection induces an accelerated aging of T lymphocytes, which is associated with the clinical progression to AIDS and death.

FIGURE 1

Gating scheme for measuring coexpression of CD45RA, CD27, and CD28 on CD4⁺ and CD8⁺ T cells from a representative FP. Row A shows CD3 gate on the left and CD4 and CD8 gate on the right. Row B shows CD45RA versus CD28 gated on CD4⁺ T cells (left) and CD8 T cells (right). Total CD28 and CD28 MFI were measured from these plots. Row C shows CD27 versus CD28 expression gated on CD45RA⁻ and CD45RA⁺ T cells to illustrate all phenotypes defined by the 3 differentiation markers. These plots were used to enumerate naive and memory cell frequencies.

FIGURE 2

A, percentages of CD28⁻ cells within the CD4⁺ or CD8⁺ T-cell populations in HIV-1–infected FPs, SPs, and UIs. B, CD28 MFI on CD28⁺CD4⁺ and CD28⁺CD8⁺ T cells in FPs and SPs. C, correlations between CD28 MFI values of CD28⁺CD4⁺ T cells and CD28⁺CD8⁺ T cells, in FPs and SPs. D, correlations between the percentages of CD28⁻ cells within the CD8⁺ T cells and the percentages of total CD4⁺ T cells, in FPs and SPs. The following statement applies to Figure 2–Figure 5: depicted in bar lots are medians and interquartile ranges. The P values for comparing group medians between the 2 HIV-1–infected groups or between the combined groups of HIV-1 infected and uninfected were calculated by the Wilcoxon signed rank test (P^#) and the Wilcoxon rank sum test (P^&), respectively. Spearmen rank correlation test was used to determine correlations.

FIGURE 3

A, percentages of CD57⁺ cells within the CD4⁺ or CD8⁺ T cells. B, percentages of CD8⁺ T-cell subsets defined by expression patterns of CD28 and CD57.

FIGURE 4

A, percentages of various CD8⁺ T-cell subsets representing differentiation stages defined by the expression of CD45RA, CD27, and CD28. B, percentages of CD4⁺ T cells are positively correlated with the percentages of naive CD8⁺ T cells (CD45RA⁺CD27⁺CD28⁺) and inversely correlated with the percentages of late-CD45RA⁻ CD8⁺ T cells (CD45RA⁻CD27⁻CD28⁻) in HIV-1– infected individuals.

FIGURE 5

A, on the left, naive CD4⁺ T cells (CD45RA⁺CD27⁺) was gated in Q2. On the right, the CD31⁺ percentages and MFI on naive CD4⁺ T cells were shown for a paired SP and FP, respectively. B, percentages of RTE (CDRA⁺ CD27⁺CD31⁺CD4⁺) and peripherally expanded naive cells (CD45RA⁺CD27⁺CD31⁻CD4⁺) within the CD4⁺ T cells or the naive CD4⁺ T cells. C, CD31 MFI on RTE (CDRA⁺CD27⁺CD31⁺CD4⁺) in FPs is lower than that of SPs.