Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy

Abstract

Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment.

Down-regulation of CD8+ T-cell expansions in patients with human immunodeficiency virus infection receiving highly active combination therapy

“…The latter clones and novel CD8 amplifications are detected on HIV reactivation. Taken together, the high prevalence of thymic tissue in adults with HIV-1, 33 the observed transient renewal of thymopoiesis in infected thymic implants during HAART, 34 the slow peripheral increase in CD4 and CD8 cell counts under treatment, 15,35 and the progressive repertoire reorganization we describe during treatment and after relapse show that restoration of the immune system is possible in chronically infected patients, if HIV replication is kept under control. Our results also indicate that the antigenic pressure responsible for repertoire skewing is lifted long before HIV can actually be eradicated from the body.…”

Targeting c-Mpl for Revival of Human Immunodeficiency Virus Type 1-Induced Hematopoietic Inhibition When CD34+Progenitor Cells Are Re-Engrafted into a Fresh Stromal Microenvironment In Vivo

“…The secondary SCID-hu recipient animals that were irradiated and re-engrafted received treatment with two antiretroviral drugs to prevent secondary infection that might be carried over from the previously virus-exposed CD34 ϩ cells of the primary implants by any contaminating traces of viral particles and to halt further virus replication. The combination drug treatment used was similar to but at reduced doses from that previously described (28,57) and included the following: protease inhibitor indinavir sulfate (Merck, Rahway, N.J.) at an approximate dose of 0.45 mg/kg of body weight/day was diluted into drinking water (pH 3) at a concentration of 1.5 mg/ml, which corresponds to a dose of 20 mg/kg/day (28,57); zidovudine (Aldrich Chemical Co., Milwaukee, Wis.) was delivered in drinking water (0.05 mg/ml) at a calculated dose of 10 mg/kg/day, based on an estimate of consumption of 3 ml of water/day/animal. The drug doses were calculated based on an average weight of 20 g/mouse.…”

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

“…Taken together, these data demonstrate a time-dependent decrease in CD8␣␤ expression on SP8 thymocytes that is related to HIV-1-induced IFN-␣ mediated up-regulation of MHC I expression in the infected human thymus. Treatment of SCID-hu Thy/Liv mice with highly active retroviral therapy (HAART) has been shown to significantly suppress active HIV-1 replication and to reverse thymocyte depletion in the SCID-hu Thy/Liv mouse model (35). Reasoning that suppression of viral replication by HAART should also result in the downregulation of MHC I and the normalization of CD8 expression on SP8 thymocytes, HIV-1-infected SCID-hu Thy/Liv mice were provided combination antiretroviral therapy 21 days after HIV-1 inoculation.…”