It has recently been shown that rapid and profound CD4؉ T-cell depletion occurs almost exclusively within the intestinal tract of simian immunodeficiency virus (SIV)-infected macaques within days of infection. Here we demonstrate (by three-and four-color flow cytometry) that this depletion is specific to a definable subset of CD4 ؉ T cells, namely, those having both a highly and/or acutely activated (CD69 ؉ CD38 ؉ HLA-DR ؉ ) and memory (CD45RA ؊ Leu8 ؊ ) phenotype. Moreover, we demonstrate that this subset of helper T cells is found primarily within the intestinal lamina propria. Viral tropism for this particular cell type (which has been previously suggested by various studies in vitro) could explain why profound CD4 ؉ T-cell depletion occurs in the intestine and not in peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate that an acute loss of this specific subset of activated memory CD4 ؉ T cells may also be detected in peripheral blood and lymph nodes in early SIV infection. However, since this particular cell type is present in such small numbers in circulation, its loss does not significantly affect total CD4 ؉ T cell counts. This finding suggests that SIV and, presumably, human immunodeficiency virus specifically infect, replicate in, and eliminate definable subsets of CD4 ؉ T cells in vivo.

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.

In this report, three Mamu-A*01؉ rhesus macaques were examined to compare the emergence of simian immunodeficiency virus (SIV)-specific CD8 ؉ T cells in the intestines and blood in early SIV infection using a major histocompatibility complex class I tetramer complexed with the Gag 181-189 peptide. Fourteen days after intravenous inoculation with SIVmac251, large numbers of SIV Gag 181-189 -specific CD8؉ T cells were detected in the intestinal mucosa (3.1 to 11.5% of CD3 ؉ CD8 ؉ lymphocytes) as well as in the blood (3.1 to 13.4%) of all three macaques. By 21 days postinoculation, levels of tetramer-binding cells had dropped in both the intestines and blood. At day 63, however, levels of SIV Gag 181-189 -specific CD8 ؉ T cells in the intestines had rebounded in all three macaques to levels that were higher (8.6 to 18.7%) than those at day 21. In contrast, percentages of tetramer-binding cells in the peripheral blood remained comparatively stable (2.5 to 4.5%) at this time point. In summary, SIV Gag 181-189 -specific CD8 ؉ T cells appeared in both the intestinal mucosa and peripheral blood at a comparable rate and magnitude in primary SIV infection. Given that the intestine is a major site of early viral replication as well as the site where most of the total body lymphocyte pool resides, these data indicate that it is also an early and important site of development of antiviral immune responses.