CD8+ T Cell Dynamics during Primary Simian Immunodeficiency Virus Infection in Macaques: Relationship of Effector Cell Differentiation with the Extent of Viral Replication

Abstract

Immunological and virological events that occur during the earliest stages of HIV-1 infection are now considered to have a major impact on subsequent disease progression. We observed changes in the frequencies of CD8bright T cells expressing different chemokine receptors in the peripheral blood and lymph nodes of rhesus macaques during the acute phase of the pathogenic SIVmac251 infection; the frequency of CD8bright T cells expressing CXCR4 decreased, while the frequency of those expressing CCR5 increased. These reciprocal changes in chemokine receptor expression were associated with changes in the proportion of cycling (Ki67+) CD8bright T cells, and with the pattern of CD8bright T cell differentiation as defined by expression of CCR7 and CD45RA. In contrast, during the primary phase of the attenuated SIVmac251Δnef infection, no major change was observed. Whereas during the acute phase of the infection with pathogenic SIV (2 wk postinfection) no correlate of disease protection was identified, once the viral load set points were established (2 mo postinfection), we found that the levels of cycling and of CCR5- and CXCR4-positive CD8bright T cells were correlated with the extent of viral replication and therefore with SIV-infection outcome. Our data reveal that, during primary SIV infection, despite intense CD8 T cell activation and an increase in CCR5 expression, which are considered as essential for optimal effector function of CD8+ T cells, these changes are associated with a poor prognosis for disease progression to AIDS.

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

“…Several lines of evidence indicate that the effectiveness of virus-specific immune responses is not only based on the quantity but also on the quality of T cells. 17,20,21 One major finding of our study provides strong evidence that Mes LNs represent major reservoirs not only for animals progressing more rapidly toward AIDS but also in LTNP, in which plasma viral loads were below the level of detection for extended periods of time. The extent of viral replication in the other organs is markedly lower, whereas viral dissemination to non-lymphoid organs appeared only later in the course of SIV infection in macaques of Chinese origin.…”

“…TIA-1 that is functionally related to perforin has been shown to be expressed by effector/ memory cells. 17 As shown in Figure 7, the extent of immunohistochemical staining in Mes LNs was greater in SIV-infected macaques than in healthy macaques. Staining with mAbs to CD8 revealed that TIA-1 expression colocalized within the CD8 T-cell zone.…”

“…However, we attempted to minimize this issue by performing the analysis of expression of TIA-1 in situ, rather than in isolated lymphocytes, since the isolation procedure itself might have induced degranulation. Most importantly, we found that the TIA-1 þ -defined effector/memory CD8 þ T cells, 17 from Mes LNs, were abnormally primed for death in SIV-infected monkeys, with higher priming in non-controllers than in controllers. Thus, we demonstrated that in addition to peripheral blood, [26][27][28] CD8 þ T cells from secondary lymphoid organs are more prone to die during chronic SIV infection.…”

“…Antibodies were added to the cells and incubated, as previously described. 17 For intracellular staining, the cells were fixed and permeabilized before incubation with anti-Ki67-FITC (clone MIB-1, Coultronics), or unlabeled anti-phospho-p53 (Ser15, Cell Signalling), Bax (BD biosciences), Bak (Calbiochem) and PUMA (Stressgen). After washing, FITC-labeled goat anti-rabbit IgG antibody was added to anti-phospho-p53.…”

AIDS Progression Is Associated with the Emergence of IL-17–Producing Cells Early After Simian Immunodeficiency Virus Infection

“…Thereafter, at day 60, IL-17-as well as TGF-bexpressing cells decreased both in Ax and Mes LNs but remained higher than preinfection. By analyzing a group of 12 monkeys (24,25) at day 14, we found a positive correlation between the numbers of IL-17-expressing cells and the numbers of TGF-b-expressing cells in Ax LNs of SIV + RM, whereas no correlation was observed with the extent of viral replication in LNs (Fig. 1H).…”