This work was supported in part by the National Institute of Allergy and Infectious Diseases (R56AI100765, R21 AI087035, R21AI078774, RO1 AI087145, K24AI069994, P01AI076174), National Institutes of Mental Health (R01 MH54907), the Doris Duke Charitable Foundation (Clinical Scientist Development Award #2008047), the University of California San Francisco (UCSF)/Gladstone Institute of Virology & Immunology Centers for AIDS Research (CFAR) (grant number P30 AI027763), the UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131), the Center for AIDS Prevention Studies (P30 MH62246), and the CFAR Network of Integrated Systems (R24 AI067039).
Cytomegalovirus infections, AIDS (Disease) -- Effect on T cell expression, AIDS (Disease) -- Treatment
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.
Public Library of Science
40. Lee SA, Sinclair E, Hatano H, Hsue PY, Epling L, Hecht FM, Bangsberg DR, Martin JN, McCune JM, Deeks SG, Hunt PW. Impact of HIV on CD8+ T Cell CD57 Expression Is Distinct from That of CMV and Aging. PLoS One. 2014 Feb 27;9(2):e89444. doi: 10.1371/journal.pone.0089444. eCollection 2014. PubMed PMID: 24586783; PubMed Central PMCID: PMC3937334