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CXCR4 Receptor Expression Is More Common on Activated CD4+ T Cells than CCR5 Expression in HIV-1 Infection
Frederick Hecht*1,2,3, E Sinclair4, A Carrico5, P Moran1,3, P Hunt1,2, M Killian1, P Bacchetti6, T Ho4, S Folkman1,3, and S Deeks1,2
1Univ of California, San Francisco, US; 2Univ of California, San Francisco, US; 3Univ of California, San Francisco Osher Ctr for Integrative Med, US; 4Univ of California, San Francisco Core Immunology Lab, US; 5Univ of California, San Francisco, US; and 6Univ of California, San Francisco, US
Background: Activated CD4+ T cells
bearing chemokine co-receptors for HIV cell entry (CCR5 or CXCR4) are the
primary targets for HIV replication, but the frequency of co-receptor
expression on activated CD4+ T cells at varying CD4+ T cell
counts has not been fully evaluated.
Methods: We performed multi-parameter flow cytometry
to measure CD3, CD4, CD8, CCR5, CXCR4, CD38, and HLA-DR in 38 chronically
infected persons with HIV-1 infection who were not on treatment. The median CD4
count was 503 cells (IQR 393, 600) and median viral load was 36,460 copies/mL
(IQR 7120, 56,776).
Results: Decreasing CD4+ T cell count was
strongly correlated with increasing activation as measured by proportion of CD4+CD38+HLA-DR+
cells (r = 0.48, p = 0.002). Of the activated (CD38+HLA-DR+)
CD4+ T cells, 39% were CXCR4+ alone, 33% were CCR5+CXCR4+,
16% were CCR5+ alone, and 12% had neither receptor. Lower CD4+
T cell counts were associated with an increase in activated (CD38+HLA-DR+)
CD4+ T cells that were CCR5–CXCR4+ (r =
–0.41, p = 0.012) and dual positives (CCR5+CXCR4+
cells, r = –0.45, p = 0.006), but there was a weaker correlation
between CD4+ T cell count and CXCR4–CCR5+ CD4
cells (r = –0.3, p = 0.07). The average ratio of CXCR4- to CCR5-expressing
activated CD4+ T cells was 1.5 and did not vary significantly with
CD4 count.
Conclusions: CXCR4 expression was more common on
activated CD4+ T cells than CCR5 expression and this remained true
with lower CD4 counts. Increases in the proportion of CD4+ T cells
that were activated and expressed chemokine co-receptors helped keep the
absolute numbers of activated CD4+ T cells expressing CCR5 and CXCR4
relatively stable with CD4 counts down to 300 cells. As CD4+ T cell
counts decrease further, however, absolute numbers of activated co-receptor-positive
cells may drop. In this situation, the predominance of CXCR4 expressing
activated CD4 cells may provide more numerous targets for HIV replication, thus
offering a survival advantage to HIV variants capable of using this co-receptor
for cell entry.
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