HIV-1–specific CD8+ T cells can mature to memory in patients receiving ART. Part 5
The results support a dynamic model of T cell differentiation and maturation in well controlled persistent infections. The model is an extension of that proposed by Hamann et al. for T cell development in which CD45RA and CD27 expression was used to distinguish terminally differentiated effector from memory T cells. The extended model proposed here uses CD45RA and CD28 staining to further differentiate between acute and memory CD8+ T cells and proposes that, in well-controlled persistent infection, the acute, memory, and terminally differentiated T cell subsets are not static, as suggested by Appay et al. in a recent linear model of differentiation, but, instead, represent a dynamic system, with flux occurring between these maturation subsets in response to changes in PVL. When the antigen burden is low then, cells mature to memory. During recrudesence, some of these memory cells are recruited back into the acute subset. The distribution of EBV- and CMV-specific T cells across multiple subsets is consistent with this model. Because the distribution of T cells across the different stages of maturation changes in response to fluctuations in antigen load, it can be used as a tool to monitor immune control over the virus.
There is currently considerable interest in the potential use of therapeutic vaccines as adjunctive therapy in HIV-1 infection. It is hoped that by boosting HIV-1–specific immune responses in patients whose infection is well controlled by ART that medication might be stopped either intermittently or perhaps even indefinitely. The results of this study suggest that, although patients receiving ART with low PVLs may be clinically similar, these patients are immunologically heterogenous. Because patients with a high proportion of memory CD8+ T cells might be expected to respond more effectively to immunization than patients with predominantly acute/highly activated T cells that are less able to proliferate, it may be necessary to categorize patients according to the distribution of T cells across the various subsets. It is tempting to hypothesize that one reason for the failure of strategic therapy interruption (STI) trials to exact virologic control while not receiving ART is caused by the possibility that HIV-1–specific CD8+ T cells have not matured to a memory phenotype at the time of STI. A better strategy for future STI or therapeutic immunization studies could be to measure the maturation phenotype of HIV-1–specific CD8+ T cells before planned intervention to be certain that they have progressed to memory.