Problems and solutions to successful gene-transfer based therapies for HIV

Since the late 1980s, when the potential for intracellular immunization using genetic methods was first suggested [1], there has been a dream that someday gene transfer methods might be available for treatment of human immunodeficiency virus (HIV)-1 infection. The goals of such gene transfer would be control of HIV-1 infection without the need for chemotherapy and the protection of the immune system from further infection with HIV-1. Thus, at the minimum, it would be expected that any functional genes expressed for this purpose would have antiviral effects sufficient to control infection and able to be expressed in T lymphocytes and macrophages targeted by HIV-1.

The pathogenesis of acquired immunodeficiency syndrome (AIDS), however, is an ongoing process in which HIV-1 infection initially alters the various tissues of the immune system, including not only T lymphocytes but also the thymus, in which T cell maturation occurs. In addition, the lymph nodes and dendritic cells, which are important for immune protection, and the bone marrow, which is essential for continued immune cell propagation are altered by HIV infection. Virus progression is undoubtedly a dynamic process, and any eventual gene therapy of HIV-1 infection that seeks to use these tissues must consider the effect that HIV has during the various periods of this progression. During a period that usually takes several years, the virus infection has a selective influence on the lymphoid compartment, reduces the available numbers of T lymphocytes, and alters their function 2, 3, 4, 5, 6. The next period of pathogenesis begins with the initiation of potent anti-retroviral therapy (ART), in which there is a selective expansion of T cells during the beginning of immune reconstitution. Here, there is an antigen-driven disproportionate stimulation of CD8 and CD4 cells that leads to an aberrant immune reconstitution due to oligoclonal expansion of cells reactive to the antigens present at the time, usually HIV-1, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [7]. Finally, there is a gradual restoration of the immune repertoire toward normalcy. It is recognized that this reconstitution varies in different persons based on residual thymic function, duration of untreated HIV-1 infection, age, and other factors, and it is not clear if this ever returns to normalcy. Thus, the lymphoid populations in most need of protection from HIV-1 often have a skewed functional capacity. In the case of stem cell gene therapy approaches, the target cells depend on a site, the marrow, which may have altered or limited supportive capacity. The issues add to the problems that must be faced in bringing gene therapy approaches to the clinic.