CD4+ T cell reconstitution, T cell activation, and memory T cell subset composition in blood and gut of HIV- and ART-suppressed HIV+ patients: implications for HIV persistence in the gut
Presented by Steven Yukl (United States).
S. Yukl1,2, E. Sinclair2,3, L. Epling2,3, Q. Li4, A. Shergill1,2, K. McQuaid1,2, L. Duan4, B. Hare2,3, H. Lampiris1,2, A. Haase4, D. Havlir2,3, J. Wong1,2, PLUS Study Group
1San Francisco VA Medical Center, San Francisco, United States, 2University of California San Francisco (UCSF), San Francisco, United States, 3San Francisco General Hospital, San Francisco, United States, 4University of Minnesota, Minneapolis, United States
Background: HIV DNA and RNA levels in gut exceed those of blood by up to 10-fold. The ileum and rectum differ in HIV levels and responses to intensification, suggesting that mechanisms of persistence may vary between sites. HIV persistence could be impacted by T cell activation, absolute CD4 levels, or composition of memory Tcell subsets.
Methods: Mucosal biopsies were obtained from ileum and rectum of 8 HIV- controls and 10 ART-suppressed HIV+ patients. Isolated cells were analyzed for Tcell composition (CD3,CD4,CD8), activation (CD38,HLA-DR), and memory subpopulations (CD45RO,CCR7,CCR5,CD27) using flow cytometry. CD4 numbers were also measured by immunohistochemistry (IHC). In 2 patients, HIV DNA was measured in sorted subpopulations of memory CD4+T cells.
Results: CD4 reconstitution appears to reach normal levels in the rectum (mean CD4%: HIV+ 51.9%; HIV- 48.7%) but not the ileum (HIV+: 29.6%; HIV- 44.2%). Ileal CD4 numbers appear normal in the lymphoid aggregates but not the lamina propria. In both ileum and rectum, T cell activation remains higher than in HIV- controls:
[Mean T cell Activation, by Site and HIV Status]
|CD38+HLA-DR+ as % of CD4+T||2.8||6.1||22.2||24.7||10.1||19.4|
|CD38+HLA-DR+ as % of CD8+T||7.8||15.3||13.2||24.0||17.7||28.3|
In three HIV+ patients, the ileum harbored more effector memory (EM) CD4+Tcells (mean 41.6% of CD4+ Tcells) than the PBMC (15.4%), but similar numbers of transitional memory (TM) CD4+T cells (ileum: 11.2%; PBMC: 14.0%). HIV DNA concentrations in ileal EM(1copy/2100 cells) were 25-fold higher than in blood EM(1copy/54000).
Conclusions: T cell reconstitution and activation differ between gut sites. The higher concentration of HIV DNA in the gut is not due to increased TM cell%, but could reflect differences in the rate of infection of memory subtypes. The abnormal immune activation and lack of CD4 reconstitution in the ileum could reflect ongoing replication or chronic virus production.
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