Impact of HIV on CD8+ T cell CD57 expression is distinct from that of CMV and aging

Abstract

Background: Chronic antigenic stimulation by cytomegalovirus (CMV) is thought to increase "immunosenesence" of aging, characterized by accumulation of terminally differentiated CD28- CD8+ T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear.

Methods: We compared markers of CD8+ T cell differentiation (e.g., CD28, CD27, CCR7, CD45RA) and CD57 expression on CD28- CD8+ T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART)-suppressed HIV-infected adults with asymptomatic CMV infection.

Results: Compared to HIV-uninfected adults without CMV (n=12), those with asymptomatic CMV infection (n=31) had a higher proportion of CD28-CD8+ T cells expressing CD57 (P=0.005). Older age was also associated with greater proportions of CD28-CD8+ T cells expressing CD57 (rho: 0.47, P=0.007). In contrast, untreated HIV-infected CMV+ participants (n=55) had much lower proportions of CD28- CD8+ cells expressing CD57 than HIV-uninfected CMV+ participants (P<0.0001) and were enriched for less well-differentiated CD28- transitional memory (TTR) CD8+ T cells (P<0.0001). Chronically HIV-infected adults maintaining ART-mediated viral suppression (n=96) had higher proportions of CD28-CD8+ T cells expressing CD57 than untreated patients (P<0.0001), but continued to have significantly lower levels than HIV-uninfected controls (P=0.001). Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8+ T cells expressing CD57 declined (P<0.0001), which correlated with a decline in percent of transitional memory CD8+ T cells, and appeared to be largely explained by a decline in CD28-CD57- CD8+ T cell counts rather than an expansion of CD28-CD57+ CD8+ T cell counts.

Conclusions: Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8+ T cells, HIV inhibits this process, expanding less well-differentiated CD28- CD8+ T cells and decreasing the proportion of CD28- CD8+ T cells that express CD57.

Figure 1. Effects of CMV and age on the proportion of CD28-CD8+ T cells expressing CD57.

The proportion of CD28- and CD28-CD57+ CD8+ T cells (A), of CD28-CD8+ T cells expressing CD57 (B), and of maturational subsets of CD28- CD8+ T cells: transitional memory, T_TR, (CD28-CD27+CCR7-CD45RA-) and terminally differentiated, T_TEMRA, (CD28-CD27-CCR7-CD45RA+) CD8+ T cells (C), were compared between HIV-uninfected asymptomatic CMV-seronegative (green) and CMV-seropositive (blue) participants. Bars represent median values. The correlation between the proportion of CD28-CD8+ T cells expressing CD57 and age was also assessed among CMV-seropositive HIV-uninfected adults (D). The red line represents a linear prediction.

Figure 2. Effects of HIV and ART on CD8+ T cell subset counts.

Total CD8+ T cell and CD28- CD8+ T cell (A), CD28-CD57+ and CD28-CD57-CD8+ T cell (B), and transitional memory, T_TR, (CD28-CD27+CCR7-CD45RA-) and terminally differentiated, T_TEMRA, (CD28-CD27-CCR7-CD45RA+) CD8+ T cell (C) counts were compared between HIV-uninfected (blue), ART-suppressed (red), and untreated viremic (purple) HIV-infected individuals. All comparisons were restricted to CMV-infected participants. Bars represent median values.

Figure 3. Effects of HIV and ART on the proportion of CD28-CD8+ T cells expressing CD57.

The proportions of CD28- CD8+ T cells, CD28-CD57+ CD8+ T cells (A), of CD28-CD8+ T cells expressing CD57 (B), and of maturational subsets of CD28- CD8+ T cells: transitional memory, T_TR, (CD28-CD27+CCR7-CD45RA-) and terminally differentiated, T_TEMRA, (CD28-CD27-CCR7-CD45RA+) CD8+ T cells (C), were compared between HIV-uninfected (blue), ART-suppressed (red), and untreated viremic (purple) HIV-infected individuals. All comparisons were restricted to CMV-infected participants. Bars represent median values. The correlation between the proportion of CD28-CD8+ T cells expressing CD57 and the percent T_TR CD8+ T cells was also assessed in HIV-infected ART-suppressed participants (D).

Figure 4. Impact of initial ART-mediated viral suppression on CD8+ T cell CD57 expression and percent transitional cells.

Changes in the percent of CD28- CD8+ T cells (A), CD28-CD57+ CD8+ T cells (B), CD28-CD8+ T cells expressing CD57 (C), and CD28- transitional memory, T_TR, (CD27+CCR7-CD45RA-) CD8+ T cells (D) are plotted over the first 6 months of ART-mediated viral suppression is plotted for 45 chronically HIV-infected Ugandans initiating their first ART regimen. Individual trajectories are shown in red and median trajectories with heavy black lines. The correlation between the ART-mediated change in the proportion of CD28-CD8+ T cells expressing CD57 and the ART-mediated change in %T_TR CD8+ T cells was also assessed (E).

Figure 5. Impact of initial ART-mediated viral suppression on CD8+ T cell subset counts.

Changes in central memory, T_CM, (CD28+CD27+CCR7+CD45RA-) (A), CD28- (B), CD28-CD57- (C), and CD28-CD57+ CD8+ T cell counts (D) are plotted over the first six months of ART-mediated viral suppression for 45 chronically HIV-infected Ugandans initiating their first ART regimen. Individual trajectories are shown in red and median trajectories with heavy black lines.

Figure 6. Schematic of CD8+ T cell differentiation and CD57 expression in HIV-uninfected and HIV-infected individuals.

In HIV-uninfected and CMV-uninfected individuals, when a central memory CD8+ T cell sees its cognate antigen, it undergoes a burst of cellular proliferation and differentiation, and many - but not all - effector CD28-CD8+ T cells complete terminal differentiation and/or undergo several rounds of cell division (A). The cells that have undergone multiple rounds of proliferation and become terminally differentiated tend to express CD57. Asymptomatic CMV infection causes even greater proliferation and terminal differentiation of CD28-CD8+ T cells, resulting in multiple completed rounds of cell division and enrichment for T_EMRA cells that express CD57 (B). When CMV-seropositive individuals are infected with HIV, they experience an even greater expansion of CD28-CD8+ T cells, but a smaller proportion of these cells undergo successful proliferation and terminal differentiation, resulting in enrichment for less well-differentiated T_TR cells and lower CD57 expression on CD28- cells (C). CD57- memory CD8+ T cells are shown in orange, and cells expressing CD57 shown in green.