EARLY T CELL ONTOGENY AND HEMATOPOIESIS
Thymopoiesis
The earliest lymphoid progenitors arise from hematopoietic stem cells in the bone marrow. During T cell development, a subset of these progenitors home to the thymus and enter the parenchyma through endothelial venules that extend into the corticomedullary junction.
Although this homing process is not well understood, CXCR4, CD44, and α6 integrin have been implicated.24 After entry into the thymus, a fraction of these lymphoid progenitors become committed T cell precursors — they mature and subsequently undergo selection. Although the prevailing view is that hematopoietic stem cells are refractory to HIV infection,25,26 the virus inhibits thymopoiesis at its earliest stages. Studies performed in vitro using CD34+ stem cells cultured with thymic epithelial cells demonstrated that HIV inhibits T cell production.27 Perhaps more convincing are data generated in vivo. In the SCID-hu model, HIV infection depleted CD34+ cells before depletion of mature thymocytes.28 Notably, CD34+ cells were not found to be directly infected by HIV in this model. The latter studies highlight the indirect effects of HIV on early thymopoiesis; however, HIV also affects hematopoiesis on a more global scale.Hematopoiesis
In many cases, patients with AIDS exhibit pancytopenia involving anemia, thrombocytopenia, neutropenia, monocytopenia, and lymphocytopenia. Although evidence suggests that CD34+ hematopoietic stem cells are not efficiently infected in vivo,25,26,29-34 an M-tropic strain of HIV has been shown to infect fetal bone marrow CD34+ cells in vitro.35 These cells exhibited a reduced capacity to engraft and generate T cells in SCID-hu mice. Furthermore, the infected CD34+ cells became apoptotic and lost pluripotential characteristics in vitro.
Interestingly, these effects were reversed by administration of a tumor necrosis factor (TNF)-α inhibitor.35 Additional studies performed in vitro have confirmed that TNF-α inhibits hematopoiesis in long-term bone marrow cultures and, in addition, have shown that HIV-encoded gp120 and Nef have similar inhibitory effects.36,37 Recent investigation in vivo identified a defect in the generation of myeloid and erythroid colony-forming units in human CD34+ cells recovered from HIV-infected SCID-hu mice.38,39 Notably, this defect was transiently reversed by antiretroviral therapy.39 Based on the observation that HIV was not detected at significant levels in CD34+ cells recovered from infected SCID-hu mice in these studies, the virus seems to indirectly inhibit hematopoiesis by an ill-defined mechanism.28,38 One proposed model suggests that HIV indirectly disrupts the bone marrow microenvironment. Accordingly, long-term bone marrow cultures infected with HIV show reduced production of hematopoietic cytokines such as interleukin (IL)-6 and GM-CSF.40,41,42 Additional studies with bone marrow cultures revealed that CD34+ hematopoietic progenitors from uninfected patients can develop on infected bone marrow stroma, but CD34+ cells from infected patients cannot develop on infected bone marrow stroma.43 Overall, the indirect effects of HIV on the bone marrow microenvironment seem to be responsible for hematopoietic defects in AIDS patients.