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Hematopoietic stem cell-based gene therapy against HIV infection: promises and caveats.

Stem cell-based gene therapy of HIV infection aims at inhibiting HIV replication and the progression to AIDS by the introduction of antiviral genes in primitive hematopoietic stem cells (HSC). Ideally, after differentiation into mature blood cells, these antiviral genes should create a host-cell population that is resistant to HIV infection. Although the current gene therapy clinical trials established the safety and provided proof-of-principle for gene therapy of HIV-1 infection, the overall results have been disappointing, and many issues still remain to be resolved before this approach can be efficiently used against HIV infection. Since a significant percentage of the stem cells in the patient have to be transduced to obtain a significant impact on HIV replication, the first prerequisite for successful gene therapy of HIV-1 infection consists of increasing the amount of transduced HSCs. Further improvements in gene transfer and gene therapy strategies will probably lead to future clinical successes. On the other hand, HIV-1 infection is a very complex disease, affecting various organs in addition to the T-cells, with an impact on T-cell homeostasis that is currently not fully understood. Even at low viral loads and before the advent of clinical symptoms, a high turnover of CD4+ cells exists in HIV-infected patients with functional implications for the homeostasis of the thymus, bone marrow and T-cell homeostasis which may hamper the CD34+ HSC approach. Hence, the extent to which these alterations hamper a gene therapy approach, or can be reversed upon HAART, will determine the feasibility of future gene therapy against AIDS.