HIV-1–specific CD8+ T cells can mature to memory in patients receiving ART. Part 3
Based on the various viral infections, there is a clear relationship between antigen load and the distribution of CD8+ T cells across the various subsets. In the case of FLU and EBV, where the antigen burden is expected to be low, antigen-specific T cells were found to distribute primarily into the memory subsets. In contrast, for CMV where the antigen burden is expected to be higher, the antigen-specific T cells distributed primarily into the terminally differentiated effector subset. For the HIV-1–infected patients with PVLs >1000 copies/mL (n=8), the majority (mean, 76%) of HIV-1–specific tetramer-positive cells were of a phenotype that is associated with acute expansions.
In support of the results reported here, an “early” T cell phenotype in HIV-1 infection has been reported by others. Appay et al. and Kostense et al. have both described the persistence of CD27 expression on HIV-1–specific T cells. The work of Champagne et al. showed that HIV-1–specific T cells were predominantly CD45RA−CCR7−, whereas CMV-specific T cells were predominantly CD45RA+CCR7−. In the same study, in vitro patterns of differentiation indicated that CD45RA+CCR7− was the most advanced differentiation stage, which provided additional evidence that, for most HIV-1–infected patients, the HIV-1–specific CD8+ T cells accumulate in a preterminally differentiated state. Down-regulation of key signaling molecules, such as CD3ζ in addition to CD28, also is a feature of this early phenotype.
The basis for the failure of CD8+ T cells to mature to terminally differentiated effectors in patients with detectable PVLs is not known. Mueller et al. have recently suggested that the lack of maturation may be the consequence of an increased susceptibility to CD95/Fas-induced apoptosis. Others have postulated that the lack of maturation may be caused by the lack of HIV-1–specific CD4+ T cells, which is characteristic of the majority of chronic HIV-1–infected patients. Although there is little direct evidence for this idea, enhancement of HIV-1–specific CD8 function in vitro with interleukin-2 does suggest that CD4-mediated help could play a role. Alternatively, the lack of terminal differentiation may reflect ongoing antigenic stimulation. The initial acute response to HIV-1 does not appear to differ significantly from that of EBV or CMV, but, as HIV-1 infection evolves, the cells do not mature as they do in EBV and CMV infection, which could be a result of the relatively high levels of antigen that prevent the cells from maturing. Interestingly, 2 individuals without previous ART with detectable PVLs but with a low vRNA set point (253 and 859 copies/mL) were found to have a significant proportion of HIV-1–specific CD8+ T cells that were CD45RA−27−, which suggests that control of HIV-1 infection while not receiving ART may be associated with a more mature effector phenotype (data not shown)