Retroviral Vectors Expressing Soluble CD4: A Potential Gene Therapy for AIDS

Abstract

Retroviral vectors have been developed which produce a secreted form of the helper/inducer T-cell antigen, CD4. Amphotropically packaged vectors were used to transduce cells, and these cells were shown to express the secreted CD4 (sCD4) gene product. The sCD4 produced by the viral vectors is immunoprecipitated by monoclonal antibodies against CD4, which specifically block human immunodeficiency virus (HIV) infection of helper/inducer T cells. A direct physical interaction of vector-produced sCD4 and HIV-1 gp120 was demonstrated by coprecipitation of sCD4/gp120 with antiserum directed against HIV gp120. Furthermore, transduced cells producing sCD4 can protect HIV-susceptible cells from infection by HIV. These data suggest that gene therapy is a potential approach for the treatment of AIDS.

Gene Therapy for HIV-1 Infection

“…Furthermore, transdominant mutants of HIV-1 Tat that prevent Tat transactiviation have been developed (Fraisier et al, 1998;Pearson et al, 1990), but were never tested in clinical trials. The same is true for transdominant forms of the HIV-1 proteins Gag (Trono et al, 1989) and Vif (Morgan et al, 1990;Vallanti et al, 2005). Cellular proteins required for virus replication have also been targeted by dominantnegative mutants.…”

“…Even though inhibition of virus replication was observed in the gene-modified cells, this concept was not pursued further. A truncated soluble form of the cell surface receptor CD4 (sCD4) has been described to protect T cells from entry of laboratory-adapted strains of HIV-1, however, inhibition was less efficient for primary virus isolates (Daar & Ho, 1991;Morgan et al, 1994;Morgan et al, 1990). In a clinical phase I study recombinant soluble CD4 was administered by continuous intravenous infusion to paediatric AIDS patients.…”

“…However, the number of reports on secreted antiviral proteins in HIV-1 gene therapy is still very limited. Examples are neutralizing antibodies (Sanhadji et al, 2000), truncated soluble CD4 (Morgan et al, 1994;Morgan et al, 1990) and interferon β (Gay et al, 2004). We have recently reported the generation of an in vivo secreted antiviral entry inhibitor (iSAVE), which exerted a strong bystander effect in cell culture (Egerer et al, 2011).…”

Gene therapy for HIV infection: what does it need to make it work?

“…Several types of gene products could be envisioned, such as secreted neutralizing antibodies, soluble CD4, antiviral chemokines and small inhibitory peptides. Work in this area has been very limited [51,57,58].…”

Prospects for homologous recombination in human gene therapy

“…Its most important advantage is its very high efficiency, which has encouraged researchers to see it as the most promising tool for gene therapies. Moreover, retroviral vectors could also potentially be used for the transfer of normal or engineered genes with therapeutic value in a type of gene addition therapy of non-hereditary diseases (Culliton 1989;Morgan et al 1990;Kasid et al 1990). A big effort is currently being made to improve the retroviral system to make it suitable for human gene therapies, and important advances have been achieved.…”