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Retroviral vectors for gene therapy of AIDS and cancer
1Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center and McKnight Brain Institute, University of Florida, Gainesville 32610-0266, USA. lchang@mgm.ufl.edu
Abstract:
Both AIDS and cancer are linked to immune dysfunctions of the body which are characterized by the persistence of disease-afflicted cells. To effect a cure with novel gene therapy approaches, these diseased cells must be eliminated either directly or indirectly using cytotoxic or suicide genes, or via activation of specific immune functional cells. Retroviral vectors are useful tools for long-term genome modification owing to their ability to integrate into host chromosomes. However, most oncoretroviruses, including murine leukemia virus (MLV), require cell division to facilitate nuclear entry; this has restricted the application of murine oncoretroviral vectors to cell targets that are actively dividing. Accordingly, gene transfer into hematopoietic stem cells (HSCs) and terminally differentiated cells such as muscles, neurons and dendritic cells (DCs) has been limited with the conventional oncoretroviral vectors. The lentiviral family of retroviruses, including human immunodeficiency virus type 1 (HIV-1), has been developed into useful gene transfer tools. Lentiviral vectors carry several nuclear entry viral proteins, and therefore can target slowly-dividing and non-dividing cells. To activate immune response against cancer or HIV infection, long-term marking of the target cells is not necessary. However, to establish intracellular defense to prevent HIV infection, prolonged genetic modification of target cells such as HSCs will be required. Due to the poor transduction efficiency and the problem of transgene silencing over time with oncoretroviral vectors, most gene therapy studies for AIDS and cancer using oncoretroviral vectors remain proof-of-concept studies. Here we will discuss recent developments in the use of retroviral vectors, including HIV-1-derived lentiviral vectors, for the treatment of AIDS and cancer, and their future therapeutic potential.
Insights
Gene therapy using retroviral vectors shows promise for treating AIDS and cancer by targeting diseased cells. Lentiviral vectors offer advantages over older oncoretroviral vectors for gene transfer into various cell types.
Area of Science:
- Gene Therapy
- Retroviral Vectors
- Immunology
Background:
- Acquired immunodeficiency syndrome (AIDS) and cancer involve immune dysfunction and persistent diseased cells.
- Effective gene therapy requires eliminating these cells or activating immune responses.
- Retroviral vectors are key tools for genome modification, integrating into host DNA.
Purpose of the Study:
- To review advancements in retroviral vector applications for AIDS and cancer gene therapy.
- To compare the capabilities of oncoretroviral and lentiviral vectors in gene transfer.
- To discuss the future therapeutic potential of these vectors.
Main Methods:
- Utilizing retroviral vectors for gene transfer into target cells.
- Comparing oncoretroviral vectors (e.g., MLV) with lentiviral vectors (e.g., HIV-1 derived).
- Evaluating vector efficiency in dividing versus non-dividing cells, including hematopoietic stem cells (HSCs) and dendritic cells (DCs).
Main Results:
- Oncoretroviral vectors require cell division, limiting their use in non-dividing cells like HSCs, muscles, neurons, and DCs.
- Lentiviral vectors, with nuclear entry proteins, can transduce slowly-dividing and non-dividing cells.
- Oncoretroviral vectors face challenges like poor transduction efficiency and transgene silencing, hindering clinical application.
Conclusions:
- Lentiviral vectors offer broader applicability for gene therapy in AIDS and cancer due to their ability to target non-dividing cells.
- Gene therapy holds significant potential for treating immune-related diseases like AIDS and cancer.
- Further development of retroviral vectors is crucial for advancing therapeutic strategies.