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Clinical Trial
. 2013 Nov 22;5(11):2898-919.
doi: 10.3390/v5112898.

Development of hematopoietic stem cell based gene therapy for HIV-1 infection: considerations for proof of concept studies and translation to standard medical practice

David L DiGiusto  1 , Rodica Stan, Amrita Krishnan, Haitang Li, John J Rossi, John A Zaia
Affiliations
Clinical Trial

Development of hematopoietic stem cell based gene therapy for HIV-1 infection: considerations for proof of concept studies and translation to standard medical practice

David L DiGiusto et al. Viruses. .

Abstract

Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected RNA-based HIV-1 inhibitors in the CD4+ cells derived from GM-HSPC will protect them from HIV-1 infection and results in a sufficient immune repertoire to control HIV-1 viremia resulting in a functional cure for HIV-1/AIDS. Additionally, it is possible that the subset of protected T cells will also be able to facilitate the immune-based elimination of latently infected cells if they can be activated to express viral antigens. Thus, a single dose of disease resistant GM-HSPC could provide an effective treatment for HIV-1+ patients who require (or desire) an alternative to lifelong antiretroviral chemotherapy. We describe herein the results from several pilot clinical studies in HIV-1 patients and our strategies to develop second generation vectors and clinical strategies for HIV-1+ patients with malignancy who require ablative chemotherapy as part of treatment and others without malignancy. The important issues related to stem cell source, patient selection, conditioning regimen and post-infusion correlative studies become increasingly complex and are discussed herein.

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Figures

Figure 1
Figure 1
Sustained engraftment and expression of anti-HIV genes in the peripheral blood of patients for up to three years after transplantation. (A) Level of gene marking expressed as number of copies of vector (WPRE) per 100 blood cells analyzed over time. Unique patient identifiers are listed in the upper right hand corner of graph. Limits of quantification (stippled) and limits of detection (diagonal lines) values were determined for each amplification reaction and typically were in the range of 0.05% (500 cells/million) and 0.01% (100 cells/million), respectively. (B) Expression of shRNA against tat/rev sequences in the blood and marrow of UPN0306 at 36 months. Results expressed as copies of shRNA per 8 ng of total RNA. PBMC—peripheral blood mononuclear cells, PBGC—peripheral blood granulocytic cells, BMMC—bone marrow mononuclear cells, BMGC—bone marrow granulocytic cells. Bar height in B is mean of triplicates ± SEM.
Figure 2
Figure 2
Monitoring of viral loads, CD4 counts and gene marking during structured treatment interruption. (A) HIV copies/mL of patient plasma (red circles, left Y axis) and CD4 counts/mm3 (green triangles, right Y axis) during treatment interruption. (B) Gene marking expressed as copies of vector (WPRE) per 100 blood cells analyzed over time. Arrow indicates time of resumption of cART.
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References

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