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Review
. 2015 Jul 17;7(7):3910-36.
doi: 10.3390/v7072804.

Bone Marrow Gene Therapy for HIV/AIDS

Elena Herrera-Carrillo  1 , Ben Berkhout  2
Affiliations
Review

Bone Marrow Gene Therapy for HIV/AIDS

Elena Herrera-Carrillo et al. Viruses. .

Abstract

Bone marrow gene therapy remains an attractive option for treating chronic immunological diseases, including acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV). This technology combines the differentiation and expansion capacity of hematopoietic stem cells (HSCs) with long-term expression of therapeutic transgenes using integrating vectors. In this review we summarize the potential of bone marrow gene therapy for the treatment of HIV/AIDS. A broad range of antiviral strategies are discussed, with a particular focus on RNA-based therapies. The idea is to develop a durable gene therapy that lasts the life span of the infected individual, thus contrasting with daily drug regimens to suppress the virus. Different approaches have been proposed to target either the virus or cellular genes encoding co-factors that support virus replication. Some of these therapies have been tested in clinical trials, providing proof of principle that gene therapy is a safe option for treating HIV/AIDS. In this review several topics are discussed, ranging from the selection of the antiviral molecule and the viral target to the optimal vector system for gene delivery and the setup of appropriate preclinical test systems. The molecular mechanisms used to formulate a cure for HIV infection are described, including the latest antiviral strategies and their therapeutic applications. Finally, a potent combination of anti-HIV genes based on our own research program is described.

Keywords: HIV-1; RNAi; antiviral; bone marrow; gene therapy; hematopoietic stem cell (HSC); lentiviral vector; virus.

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Figures

Figure 1
Figure 1
Target cells for an anti-HIV gene therapy. Shown is the scheme of hematopoiesis. Either hematopoietic stem cells (HSCs) from bone marrow or the mature CD4+ T cells can be targeted. These two cell populations are boxed.
Figure 2
Figure 2
Steps of the HIV-1 replication cycle that can be targeted by gene therapy. The HIV-1 replication steps that can be targeted by gene therapy are shown: (1) HIV-1 binding to cell membrane; (2) HIV-1 entry into the cell; (3) reverse transcription; (4) transport of the HIV-1 proviral genome into the nucleus; (5) integration of the viral genome into the cellular DNA; (6) transcription of the HIV-1 proviral genome; (7) translation of the viral messenger RNA (mRNA) into new viral proteins; (8) virion assembly inside the cell; and (9) maturation of the immature virion into a completely infectious particle.
Figure 3
Figure 3
The endogenous miRNA and exogenous shRNA processing pathways. The intracellular processing pathways are depicted starting from the miRNA gene of the cell (endogenous) or the transduced shRNA gene cassette (exogenous). The canonical Dicer-dependent and noncanonical Dicer-independent pathways are depicted for both molecules. Ago2 plays an essential role in Dicer-independent pathways. See the text for further details. PACT: Protein activator of protein kinase R; Pri-miRNA: Primary miRNA; Ago2: Argonaute 2 nuclease; RISC: RNA-induced silencing complex; TRBP: Transactivation response RNA-binding protein.
Figure 4
Figure 4
Combinatorial RNAi strategies. Four inhibitory scenarios are plotted with the respective advantages and disadvantages. This figure was adapted from [111]. LV: lentiviral vector.
Figure 5
Figure 5
Self-inactivating lentiviral vectors for stable shRNA expression. (A) The lentiviral vector JS1 is shown with three plasmids needed for lentiviral vector production. The vector genome is expressed from the Rous Sarcoma Virus (RSV) promoter. Transcripts start with the HIV-1 R and U5 regions and the packaging signal (ψ). The enhanced green fluorescent protein (GFP) reporter is expressed from the phosphoglycerate kinase promoter (PGK). Transcription of the vector genome and the GFP reporter terminates at the HIV-1 polyA signal within the 3′ LTR; (B) Scheme of a hematopoietic stem cell (HSC) clinical trial. An HIV-infected patient who fails on regular drug therapy will undergo apheresis for the collection of CD34+ HSC after pretreatment with granulocyte-colony stimulatory factor (G-CSF). The mixed cell population containing CD34+ HSC will be purified and transduced ex vivo with the therapeutic construct. Transduced cells will be infused back into the patient and the antiviral gene should protect these cells against HIV-1.
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