EFFECTS OF ANTI-HIV THERAPY ON THE THYMUS HAART
Highly active antiretroviral therapy (HAART) employing a reverse transcriptase inhibitor in conjunction with two or more protease inhibitors has proven extremely effective in controlling HIV replication.
Patients who respond favorably to HAART exhibit a reduction in viral load and a rebound in peripheral blood CD4 counts. Specifically, responders were found to be younger, have a larger thymus according to CT scan, and produce more naive CD45+, CD62L+, CD4, and CD8 T cells.104 In addition, naive CD4 cells derived from responders contained more TRECs than nonresponders.104 Metabolic labeling with deuterated glucose and measurement of telomere lengths in CD4 T cells demonstrated that the reduced TREC levels observed in nonresponders could not be explained by excessive T cell proliferation.104 Several groups have reported an increase in thymic function after HAART. In these studies, RTEs identified according to phenotypic markers and the presence of TRECs were found at higher levels in HAART patients than in untreated controls.105-107 Additional studies reported increases in thymic volume and naive T cell counts in HIV+ patients after HAART.105,108 Interestingly, HAART was also shown to expand the TCR repertoire in AIDS patients.109 These results raise the question of whether or not HAART increases thymic function by reducing viremia, by directly boosting thymic function, or both. HIV protease inhibitors were shown to directly inhibit apoptosis in peripheral T cells by antagonizing the mitochondrial permeability transition pore complex.110-113 If protease inhibitors inhibit thymocyte apoptosis by a similar mechanism, thymic output may increase, but autoreactive thymocytes could escape negative selection as well. In fact, cases of autoimmunity have been observed in AIDS patients receiving HAART.19 Additional observations were interpreted to suggest that HAART directly promotes thymic output independent of its effects on HIV. For example, failure of HAART to reduce viremia does not always preclude increases in thymic volume, TREC levels, or naive T cell counts.113 However, protease inhibitor-resistant strains of HIV have been shown to be less pathogenic to the thymus than protease-inhibitor-sensitive strains.114,115 The implication is that a failure of HAART to control protease inhibitor-resistant HIV does not rule out the possibility that HAART inhibits replication of thymus-trophic HIV variants within the same individual. Thus, HAART may increase thymic output by controlling viremia and not necessarily by inhibiting thymocyte apoptosis. Furthermore, Amado et al. reported that the protease inhibitor indinavir did not increase thymic output in uninfected SCID-hu mice.116 Studies performed in our laboratory suggest that the protease inhibitor nelfinavir does not inhibit TCR-mediated apoptosis in murine thymocytes (Graham et al., manuscript in preparation). Additional studies will be necessary to determine whether or not HAART increases thymic output by simply inhibiting HIV replication or by alternative mechanisms.Cytokines
Recently, clinical trials supplementing HAART with cytokine therapy were undertaken with the intent to bolster immune reconstitution. IL-2 administration in conjunction with HAART increased CD4 counts compared with HAART alone.117-120 Additionally, TREC levels in patients treated with IL-2 and HAART decreased or remained stable, suggesting that peripheral expansion is responsible for recovery of the CD4 T cell population.117,119,120 In the absence of HAART, IL-2 treatment increased CD4 counts yet decreased thymic volume.121 IL-2 treatment in SCID-hu mice infected with HIV transiently maintained relative percentages of DP thymocytes and more immature thymocytes, whereas IFN-γ treatment transiently maintained mature CD3+CD69+ thymocytes.122 The latter study also demonstrated that IL-4 or IL-7 treatment delayed thymocyte depletion but increased viral load.122 Several novel treatment strategies designed to augment thymic function have been attempted.
Administration of growth hormone can increase thymic mass and CD4 counts in humans infected with HIV.123 Additionally, AIDS patients have been treated with various thymic hormones in attempts to restore thymic function, but results have shown minimal to no benefit.124-130 It has also been postulated that AIDS patients may be amenable to thymic transplants due to their immunosuppressed condition. One study suggested that thymic grafts absent of T cells and fibroblasts were well tolerated and enhanced the clinical status of patients.131 However, a more recent study demonstrated that allogeneic thymic tissue transplanted into HIV+ recipients was rejected within 2 months and failed to restore T cell counts.132 Ultimately, effective strategies to augment thymic function remain elusive.