Dynamics of CCR5 Expression by CD4⁺T Cells in Lymphoid Tissues during Simian Immunodeficiency Virus Infection

Abstract

Early viral replication and profound CD4؉ T-cell depletion occur preferentially in intestinal tissues of macaques infected with simian immunodeficiency virus (SIV). Here we show that a much higher percentage of CD4 ؉ T cells in the intestine express CCR5 compared with those found in the peripheral blood, spleen, or lymph nodes. In addition, the selectivity and extent of the CD4 ؉ T-cell loss in SIV infection may depend upon these cells coexpressing CCR5 and having a "memory" phenotype (CD45RA ؊ ). Following intravenous infection with SIVmac251, memory CD4 ؉ CCR5 ؉ T cells were selectively eliminated within 14 days in all major lymphoid tissues (intestine, spleen, and lymph nodes). However, the effect on CD4 ؉ T-cell numbers was most profound in the intestine, where cells of this phenotype predominate. The CD4 ؉ T cells that remain after 14 days of infection lacked CCR5 and/or were naive (CD45RA ؉ ). Furthermore, when animals in the terminal stages of SIV infection (with AIDS) were examined, virtually no CCR5-expressing CD4؉ T cells were found in lymphoid tissues, and all of the remaining CD4 ؉ T cells were naive and coexpressed CXCR4. These findings suggest that chemokine receptor usage determines which cells are targeted for SIV infection and elimination in vivo.

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

“…Finally, most DP cells in the intestine are memory cells. Memory CD4 + T cells have been shown to be selectively infected in SIV and HIV [1,[40][41][42]. Combined these observations support our earlier data suggesting that DP T cells in the intestine are rapidly eliminated in early SIV infection due to their increased expression of viral co-receptors and their higher level of activation [1].…”

“…Higher expression of activation markers (HLA-DR, CD69 and CD25) has previously been reported on intestinal CD4 + T cells from neonatal and adult macaques [1,39]. Intestinal DP T cells also had higher expression of CCR5.…”

“…Rapid depletion of intestinal DP cells occurs faster and more profoundly than that of intestinal CD4 + singlepositive (SP) cells which we have previously correlated with increased levels of CCR5 expression on the former [1]. Although DP T cells have been described in the blood and intestine of humans, nonhuman primates, swine and rodents [2][3][4][5][6][7][8][9][10][11][12], little is known regarding their function or immunophenotypic (naive versus memory status etc.)…”

“…CD4 + CD8 + double positive (DP) T cells in the intestine have been shown to be a major early target in primary simian immunodeficiency virus (SIV) infection [1]. Rapid depletion of intestinal DP cells occurs faster and more profoundly than that of intestinal CD4 + singlepositive (SP) cells which we have previously correlated with increased levels of CCR5 expression on the former [1].…”

Apoptosis in SIV infection

“…164,165 It has been also reported that T-cell depletion in peripheral blood during primary infection was related to T cells expressing CCR5. [166][167][168] However, this latter observation remains controversial. 169 Since HIV-1 does not replicate efficiently in non-human primate species, chimeric simian-human immunodeficiency viruses (SHIVs) have been created that can infect NHPs.…”