Antigen Burden Is a Major Determinant of Human Immunodeficiency Virus–Specific CD8+ T Cell Maturation State. Part 2
An obvious potential correlate is an enhanced HIV-1–specific immune response in terms of magnitude. However, it has been difficult to correlate the magnitude of the T cell response with effective control of infection in untreated HIV-1–infected individuals. Although some studies have reported an inverse correlation between PVL and levels of HIV-1–specific T cell responses, other studies have not confirmed these relationships. The results, when taken together, suggest that the magnitude of the T cell response may not necessarily correlate with clinical outcome, which, in turn, has led to an interest in identifying qualitative aspects of the immune response that might correlate with effective control of the virus
Recent advances in the detection of antigen-specific T cell responses have allowed the dissection of the T cell response during the course of a variety of viral infections. In both rapidly resolved and persistent but well controlled viral infections, T cells appear to pass through a series of maturation steps as the virus is brought under control. As the cells pass through these maturation stages, they exhibit distinct cell surface phenotypes. In particular, cell surface molecules, such as CD45RA/RO, CD28, and CD27, which play a role in modulating the signaling threshold of the cell, are differentially expressed throughout these different stages of T cell maturation. The acute and highly activated CD8+ T cells found in the initial phase of infection are CD45RA−, CD45RO+, CD27+, and CD28−. A proportion of these acute and highly activated CD8+ T cells can go on to lose CD27 expression as they gain full lytic potential and mature into terminally differentiated CD8+ T cells. It is now clear from T cell activation studies, as well as studies using tetrameric forms of major histocompatibility complex (MHC) class I molecules, that these terminally differentiated CD8+ T cells usually revert from CD45RO to CD45RA expression. Therefore, terminally differentiated effector T cells are characterized by a CD45RA+, CD45RO−, CD27−, and CD28− phenotype. As the infection resolves, the memory CD8+ T cells that ultimately emerge are CD27+, CD28+, and, often, CD45RO+, although these cells also can revert from CD45RO to CD45RA expression. Memory cells then are characterized by a CD45RA− and CD45RO+ or a CD45RA+, CD45RO−, and CD27+CD28+ phenotype. Therefore, combined staining for specific combinations of these markers can distinguish effector, memory, and recently activated CD8+ T cell maturation subsets
We hypothesized that, in persistent viral infections, these T cell maturation subsets will represent a dynamic system with the antigen-specific CD8+ T cells moving among the acute, effector, and memory subsets in response to changes in PVL. Thus, if there has been a recent burst of viral replication, the cells would distribute primarily between the acute and effector subsets, and, if a significant period of time has passed since a burst of viral replication, the cells would be found primarily in the memory subset. If this were the case, then staining for these markers could be used in combination with tetramer staining as an indication of the degree of control over virus infection