Inhibition of Human Immunodeficiency Virus Replication and Growth Advantage of CD4 + T Cells from HIV-Infected Individuals That Express Intracellular Antibodies Against HIV-1 gp120 or Tat

Abstract

Current clinical gene therapy protocols for the treatment of human immunodeficiency virus type 1 (HIV-1) infection often involve the ex vivo transduction and expansion of CD4⁺ T cells derived from HIV-positive patients at a late stage in their disease (CD4 count <400). These protocols involve the transduction of T cells by murine leukemia virus (MLV)-based vectors encoding antiviral constructs such as the rev m10 dominant negative mutant or a ribozyme directed against the CAP site of HIV-1 RNA. We examined the efficiency and stability of transduction of CD4⁺ T cells derived from HIV-infected patients at different stages in the progression of their disease, from seroconversion to AIDS. CD4⁺ T cells from HIV-positive patients and uninfected donors were transduced with MLV-based vectors encoding β-galactosidase and an intracellular antibody directed against gp120 (sFv 105) or Tat. (sFvtat1-C _κ ). The expression of marker genes and the effects of the antiviral constructs were monitored in vitro in unselected transduced CD4⁺ T cells. Efficiency and stability of transduction varied during the course of HIV infection; CD4⁺ T cells derived from asymptomatic patients were transducible at higher efficiencies and stabilities than CD4⁺ T cells from patients with acquired immunodeficiency syndrome (AIDS). Expression of the anti-tat intracellular antibody was more effective at stably inhibiting HIV-1 replication in transduced cells from HIV-infected individuals than was sFv 105. The results of this study have important implications for the development of a clinically relevant gene therapy for the treatment of HIV-1 infection.

Overview summary

This study examined the efficiency and stability of transduction of T cells from human immunodeficiency virus (HIV)-infected individuals with a murine leukemia virus based vector encoding an anti-HIV intracellular antibody to gp120 (sFvl05), or to Tat (sFvtatl-C _κ ). The paper demonstrates that T cells, derived from HIV-positive patients, were stably transduced with the transgene and that they were protected from HIV infection by the presence of the gene encoding the anti-HIV intracellular antibody. The results of this paper provide proof of principle that an anti-HIV intracellular antibody can be used as a putative gene therapeutic agent to protect CD4⁺ T cells from HIV-infected individuals. Therefore, this data provides support for a proposed clinical phase 1 study of a gene therapy for HIV infection utilizing the transduction and ex vivo expansion of T cells with a construct encoding an anti-HIV intracellular antibody.