A recombinant adenoviral vector with a specific tropism to CD4-positive cells: a new tool for HIV-1 inhibition.

Abtin Behmardi,Touraj Farazmandfar

doi:10.1007/s13346-021-01109-y

Abstract

Gene therapy can be an option to overcome the side effects of chemotherapy and prevent the development of drug-resistant HIV viruses in HIV-infected patients. The need to develop a safe and efficient vector for gene transfer is always necessary and an appropriate option might be adenovirus (Ad). The use of Ad vectors in gene delivery applications is limited due to the semi-specific tropism. A strategy to overcome this tropism limitation may be the modification of the fiber protein domain involved in the viral binding to cells. Therefore, we designed an Ad5 vector with a specific tropism to CD4 + cells containing an expression system limited to HIV-infected cells. We replaced the knob region of Ad5 fiber protein with the extracellular region of the HIV-1 envelope. We also used a specific Tat-inducible promoter to express two anti-HIV-1 shRNAs. Tropism of recombinant Ad5 was assayed by a comparison of the shRNA expression level in CEM and PBMC cells (as CD4 + cells) and HEK293 cells (as CD4 cells). HIV-1 inhibition was assayed by the determination of p24 antigen in the HIV-infected CEM cells transduced with the recombinant Ad5 vector. Our results showed that the shRNA expression was significantly higher in CEM and PBMC cells than HEK293 cells when transduced with recombinant Ad5 vector. This new Ad5 vector also inhibited HIV-1 proliferation in a Tat-inducible manner. Our new recombinant Ad5 vector has a specific tropism to CD4-positive cells that can effectively suppress the HIV-1 replication.

Highlights

The acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is one of the acute problems of today's world that should be considered
Our results showed that shRNA expression was significantly higher in CEM and peripheral blood mononuclear cells (PBMC) cells than HEK293 cells when were transduced with recombinant Ad5 vector
Recombinant Ad5 vector has a specific tropism to CD4-positive cells

Summary

Introduction

The acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is one of the acute problems of today's world that should be considered. There is a need to develop new alternative therapies to cure patients with chronic HIV infection One of these advanced therapies is genetic-based approaches such as the use of suicide genes [4, 5], dominant-negative proteins [6, 7], and oligonucleotide-based materials [8, 9]. Given the main problem in controlling HIV infection is the ability of the virus to resist drugs and avoid treatment, so the need to design strategies to control virus replication seems essential These strategies can include targeting the different viral products in early and late steps of the virus life cycle, designing RNAs interference (RNAi) against the conserved regions on virus transcripts, or a combination of the two strategies. These strategies have shown that they can remarkably reduce the escape of the mutated virus [10, 11]

Methods

Results

Conclusion