Treatment Issues: Newsletter of Current Issues in HIV/AIDS - Volume 18, Number 1 & 2, January / February 2004
Bob Huff

Resistance to RNAi inhibition of HIV
Atze Das and colleagues from the University of Amsterdam reported in the Journal of Virology that they had successfully expressed small interfering RNAs (siRNA) targeted to the HIV Nef gene that blocked viral replication in long-term experiments. RNA interference is a recently discovered natural process where short (22 base pair) double strands of RNA can target complementary sequences of messenger RNA and prevent their translation into proteins. Previously, siRNA has been shown to be an effective HIV-inhibitor in short-term assays. But the inhibition of replication is not complete, apparently, since escape mutants were observed to appear after several weeks in culture. The resistant viruses had changes or deletions in the Nef sequence, which could evade control by the experimental siRNA. One way around this problem might be a form of combination therapy, where multiple variants of the anti-Nef siRNA sequence are introduced that would block the common resistant mutations as they emerged.

Das A, et al. "Human immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition" J Virol. 2004 Mar;78(5):2601-5.

Assay for Less-Fit Phenotype?
An experimental phenotypic drug-resistance assay could potentially model complex viral properties with much more clinically relevant information than current assays offer, particularly for people with multi-drug resistant virus. Commercially available phenotypic resistance assays evaluate drugs individually but may miss synergies resulting from combinations. A flow cytometry-based assay developed by Haili Zhang and colleagues, from Johns Hopkins University, not only reports susceptibility to complete regimens in a physiologically relevant way, but incorporates a measure of replication capacity. Some drug-resistant mutants are less replication-competent than wild-type HIV and certain "salvage" patients may benefit from remaining on therapy despite virologic failure. The assay would allow clinicians to identify which drugs in the regimen were selecting the "less fit" virus, and allow them to stop non-contributing drugs. The assay could also report if a drug combination had residual virologic effect despite the apparent lack of activity by its components.

Zhang H, et al. "Novel single-cell-level phenotypic assay for residual drug susceptibility and reduced replication capacity of drug-resistant human immunodeficiency virus type 1". J Virol. 2004 Feb;78(4):1718-29.

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