BACKGROUND:  Existing approaches used for the treatment of human immunodeficiency virus (HIV) target various viral life cycle stages including viral entry, reverse transcription, and post-translational processing steps. However, other stages of the viral life cycle have not yet been effectively targeted, thus allowing for virus that has moved through these stages to overcome current methods of therapy. One stage of the viral life cycle that is of critical importance and may represent a clinically-relevant site for therapeutic intervention is the assembly and budding of the HIV virus. Some studies have proposed that certain cells types such as dendritic cells (DCs) produce much lower levels of virus than infected CD4-positive T-lymphocytes. This suggests the presence of a defined mechanism inherent within DCs that prevents efficient viral release from infected cells. Knowledge of such a mechanism would then provide insight into strategies that could be potentially used to target this stage of the viral life cycle.

INNOVATION:  Researchers at UCLA have discovered a protein that is capable of reducing viral production of the HIV virus from infected cells. This protein has been reported to be expressed on antigen-presenting DCs. Experiments indicate that viral gene expression and protein translation are not affected, therefore suggesting an inhibition of viral assembly or budding. Medium analyzed from transfected cells containing a functional HIV genome and the gene encoding for the identified protein display very low levels of p24 Gag protein, thereby indicating a significant reduction in viral generation. It has also been determined that levels of the HIV envelope protein gp120 are efficiently decreased from the cell membrane and the viral envelope of the small number of viral particles that are generated from infected cells containing the identified protein. This data indicates that these viral particles, while still produced, are not infectious. In addition, dose-response studies indicate that this protein is a potent inhibitor of HIV infectivity. Therefore, the mechanisms that govern the observed inhibition of viral production may offer strategies in support of the development of an HIV vaccine or other methods of therapeutic intervention against HIV infection.

POTENTIAL APPLICATIONS 

• New approaches for HIV vaccine development.
• Novel applications toward the development of HIV therapies using blood stem cells, gene delivery vectors or pharmacological agents.

ADVANTAGES

• The identified mechanism is an endogenous process already inherently present in humans.
• Offers the potential of developing therapeutic approaches that may offer improved efficacy in inhibiting HIV production from infected cells with less toxicity than currently available treatments for HIV infection.

DEVELOPMENT-TO-DATE:  This method of HIV inhibition has currently been evaluated using in vitro cell culture assays.

Related Papers (Selected)

• Wang Q and Pang S. "An intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) efficiently blocks HIV viral budding." FASEB Journal. 2008; 22:1055-1064. [more]