Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo.

The mechanisms controlling neural stem cell proliferation are poorly understood. Here we demonstrate that the PTEN tumor suppressor plays an important role in regulating neural stem/progenitor cells in vivo and in vitro. Mice lacking PTEN exhibited enlarged, histoarchitecturally abnormal brains, which resulted from increased cell proliferation, decreased cell death, and enlarged cell size. Neurosphere cultures revealed a greater proliferation capacity for tripotent Pten-/- central nervous system stem/progenitor cells, which can be attributed, at least in part, to a shortened cell cycle. However, cell fate commitments of the progenitors were largely undisturbed. Our results suggest that PTEN negatively regulates neural stem cell proliferation.

HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues.

Although HIV-1 gene expression is detected in naive, resting T cells in vivo, such cells are resistant to productive infection in vitro. However, we found that the endogenous microenvironment of human lymphoid tissues supports de novo infection and depletion of this population. Cell cycle analysis and DNA labeling experiments established that these cells were definitively quiescent and thus infected de novo. Quantitation of the "burst size" within naive cells further demonstrated that these cells were productively infected and contributed to the local viral burden. These findings demonstrate that lymphoid tissues support active HIV-1 replication in resting, naive T cells. Moreover, these cells are not solely reservoirs of latent virus but are permissive hosts for viral replication that likely targets them for elimination.

Generation of HIV latency during thymopoiesis.

The use of combination antiretroviral therapy results in a substantial reduction in viremia, a rebound of CD4+ T cells and increased survival for HIV-infected individuals. However, this treatment does not result in the total eradication of HIV. Rather, the virus is thought to remain latent in a subset of cells, where it avoids elimination by the immune system. In this state the virus is capable of reactivation of productive infection following cessation of therapy. These latently infected cells are very few in number and it has thus been difficult to determine their origin and to study the molecular nature of the latent viral genome. HIV replication is linked to cellular gene transcription and requires target cell activation. Therefore, should an activated, infected cell become transcriptionally inactive prior to cytopathic effects, the viral genome might be maintained in a latent state. We used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis, a process where previously activated cells mature towards quiescence. Moreover, we showed that these cells can be exported into the periphery where the virus remains latent until T-cell receptor stimulation, indicating that the thymus might be a source of latent HIV in humans.

Generation of functional thymocytes in the human adult.

Reconstituting the immune response will be critical for the survival of HIV-infected individuals once viral load is brought under control. While the adult thymus was previously thought to be relatively inactive, new data suggest it may play a role in T cell reconstitution. We examined thymopoiesis in adults up to 56 years of age and found active T cell receptor (TCR) rearrangement, generating a diverse TCR Vbeta repertoire. The resulting thymocytes are functional and are capable of responding to costimulatory signals. These data demonstrate that the adult thymus remains active late in life and contributes functional T cells to the peripheral lymphoid pool.