Researchers at the University of Texas M.D. Anderson CancerCenter have found that a peptide of the V3 loop -- a region ofthe HIV envelope glycoprotein gp120 -- can block HIVinfection of human cells in vitro and prevent infected cellsfrom binding to healthy cells.
M.D. Anderson plans to seek FDA approval to begin clinicaltrials within the next year to determine if the peptide willwork in humans and, if it is effective, whether HIV can findanother pathway for entering the cell.
K. Jagannadha Sastry et al. reported their findings in theNovember issue of the Journal of Virology. Sastry said he andhis colleagues "aren't exactly sure how the peptide blocks HIVinfection in human cells, but it is likely that it mimics theeffects of the V3 loop in a way that prevents the virus frompenetrating cells. We believe the peptide is occupying all of theslots on the surface of a cell that would otherwise be used bythe V3 loop to attach to and introduce the virus into the cell,"Sastry said.
HIV infection begins with the envelope glycoprotein binding tothe CD4 receptor on uninfected cells, the researchers wrote."Expression of gp120 at the cell surface has also been shown toinduce cell-to-cell fusion, or syncytium formation, inappropriate cell types bearing CD4." They noted that severalreports in scientific literature have shown that the V3 loopregion of gp120 is essential for HIV-1 infection since V3 loopantibodies have been shown to inhibit infectivity andsyncytium formation, and specific mutations in the V3 looprender the virus ineffective.
The researchers attempted to determine the anti-HIV effects ofV3 loop peptides from different HIV-1 strains. They tested a15-amino acid synthetic peptide, R15K, from the V3 loop regionin HIV-1 IIIB for its effect on infection of the human Tlymphoblastoid cell lines MT-4 and CEM by HIV-1 IIIB. Thecells were pretreated with the peptide for 15 minutes beforebeing infected with the virus. "While infection of MT-4 cellswas blocked by 90 percent at a peptide concentration of 150ng/ml (0.15 ug/ml), as little as 8 ng/ml of R15K completelyinhibited infection of CEM cells by HIV-1 IIIB," the researchersstated.
Several peptides were used as negative control reagents in thestudy, including a peptide similar to R15K but with a scrambledamino acid sequence, and peptides from different HIV genes.The authors reported that these controls did not exhibit anysignificant level of inhibition of HIV.
The researchers also found that R15K was able to inhibitinfection of normal human T cells and had no direct effect onthe infectivity of the virus.
They concluded that their findings "provide support forpotential therapeutic application of V3 loop peptides becausethey not only are capable of blocking HIV infection of anumber of human cell lines and of primary human T cellsisolated from fresh healthy human blood samples but alsoinhibit cell-to-cell spread of HIV." In addition, the researcherssaid, the V3 loop peptides as a mixture "could provide theadded advantage of being an immunotherapeutic reagent" since"they are capable of inducing HIV-1 specific cytotoxic T-lymphocyte responses that can effectively kill virus-infectedcells."
-- Brenda Sandburg News Editor
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