Infection with HIV-1 causes a chronic medical condition that is associated with signs of accelerated immune aging, even when active viral replication is effectively suppressed with existing antiretroviral combination therapy. This acceleration of the physiologic aging process is most obvious in the growing population of HIV-1 infected persons who are >50 years old and projected to account for more than half of the entire HIV-1 patient population in the US and other western countries by 2015. Yet, mechanisms responsible for premature immune senescence in HIV-1 infection are insufficiently understood, and no specific clinical interventions are available at this point that may retard accelerated aging in this specific patient population. The stem cell hypothesis of aging postulates that aging predominantly reflects a decline in the frequency and function of somatic stem cells, which are able to regenerate and repopulate mature tissue cells. Phenotypic and functional signs of immune aging only seem to occur when the stem cell-mediated regeneration of tissues is exhausted and defective. Recently, a new population of lymphocellular stem cells has been identified that represents the earliest developmental stage of antigen-specific memory T cells and persist throughout lifetime to repopulate all known memory T cell subsets. A central hypothesis of this application is that accelerated aging of this novel stem cell population, termed "T memory stem cells", represents the original event from which all subsequent signs of premature cellular immune senescence during HIV-1 infection arise. To investigate this hypothesis, we will initially focus on a detailed assessment of functional and molecular characteristics of T memory stem cells, including HIV-1-specific T memory stem cells, in different populations of young and elderly HIV-1 infected persons, using cellular, molecular, genetic and functional immunologic assays (specific aim 1). Since developmental programs in T memory stem cells are governed by stem cell-specific molecular pathways, we will subsequently investigate whether the aging profile of T memory stem cells from HIV-1 patients can be manipulated and ameliorated through pharmaceutical agents that enhance stem-cell specific functional programs. For this purpose, we will expose T memory stem cells to pharmaceutical activators of the wnt/beta- catenin pathway, a phylogenetically conserved molecular program involved in regulating asymmetric cell division, multi-/pluri-potency and homeostatic proliferation of stem cells, and evaluate the resulting functional effects using a panel of established assays (specific aim 2). Although the role of T memory stem cells for immune aging is investigated in the context of HIV-1 infection in this application, our studies may go beyond HIV-1 infection and be applicable in alternative disease contexts associated with premature immune aging.
This application addresses the issue of premature aging in HIV-1 infection and its particular consequences for elderly individuals by focusing on a novel group of stem cells that represents the main regenerative source for T lymphocytes. This could lead to discovery of novel principles of stem cell-related immune aging in HIV-1 infection and clinical and translational innovations that can be used for improving HIV-1 patient care.