AIDS patients that have initiated HAART treatment can develop lung inflammatory disease (such as IRIS) as they become CD4 T cell-competent. We have recently shown that CD4 T cells, in the absence of B cells, can accumulate in the lungs of mice in response to infection by the fungi of the genus Pneumocystis (PC) resulting in severe lung damage without clearance of the PC. However, we found previously that CD4 T cells generated in immunocompetent mice and transferred to PC-infected SCID mice, clear the PC infection in the recipient mice. In addition, recent studies by Lund et al. indicate that PC-immune CD4 T cells from wild type mice passively transferred into PC-infected SCID mice clear the infection, whereas transfer of CD4 T cells from immune ?MT mice do not. These data strongly suggest that subpopulations of CD4 T cells, with different protective and damaging effector functions, can be generated in PC pneumonia. Thus, we hypothesize that as CD4 cells repopulate a CD4 T cell-deficient host, different subpopulations of CD4 T cells can be induced that vary in their ability to clear PC and/or cause lung damage. To address this hypothesis we propose to accomplish the following specific aims:
Aim 1. To describe the immune and inflammatory responses to PC infection in CD4 T cell-deficient mice as CD4 T cell numbers are restored;
Aim 2. To determine how CD4 T cell interactions with CD8 T cells, CD4 Treg cells, and B cells affects lung damage during PC-induced IRIS;
Aim 3. To determine the mechanisms by which effector CD4 T cells cause damage in the lungs. In order to rationally develop treatments to ameliorate CD4 T cell-mediated damage in the lungs in IRIS, we must understand the mechanisms by which this damage occurs. The proposed specific aims will identify cytokines, cells, cell interactions, and cell functions that are responsible for CD4 T cell-mediated lung damage such as that which occurs in IRIS. Identifying these players and the molecules that regulate these responses will in turn identify targets for therapies for conditions such as IRIS and pulmonary hypertension in AIDS patients.
Although HAART has proved successful in improving the quality of life of HIV-infected individuals, many of these patients are experiencing other problems including inflammatory disease such as IRIS and pulmonary hypertension. Our preliminary evidence indicates that these types of problems can be caused by CD4 T cells as they repopulate a previously depleted host. Studies as these proposed here will result in a better understanding of the mechanisms that cause damage to the host in these conditions which in turn can lead to the rational development of therapies to treat conditions such as IRIS and pulmonary hypertension associated with HIV infection.
|Swain, Steve D; Meissner, Nicole N; Siemsen, Dan W et al. (2012) Pneumocystis elicits a STAT6-dependent, strain-specific innate immune response and airway hyperresponsiveness. Am J Respir Cell Mol Biol 46:290-8|