An in vitro study by Aberham et al in 1996 selected HIV-1 variants that are resistant to a non-immunosuppressive analog of cyclosporin A (CsA) . The phenotype of all variants was not just drug-resistance, but full drug-dependence. The mutants selected in this study provided the first evidence that mutations in the Gag protein can confer resistance to CsA, and that these resistant variants were also critically dependent on CsA for their replication. Furthermore, the drug-dependent phenotype is very stringent, and only revertant viruses with the parental phenotype grew out in the absence of CsA. Subsequent reports proposed a mechanism of HIV-1 resistance to CsA [31,32]. Briefly, HIV-1 requires the incorporation of the peptidyl-prolyl isomerase cyclophilin A (CypA) into maturing virus particles via contact with the proline-rich domain of Capsid (CA) in the Gag polyprotein p55. Early findings on the involvement of CypA suggested that incorporation is necessary for the production of infectious virus particles [33,34]. More recent reports suggest that CypA protects HIV-1 CA from a restriction factor in human cells . The mechanism will likely await identification of this putative restriction factor .
CsA binds to CypA and inhibits its incorporation into the virion particle. Resistance to CsA occurs when HIV-1 alters the proline-rich domain in CA to effectively become CypA-independent. Although the exact mechanism of CsA-dependence is not known, numerous models have been proposed [30-32,36]. Recently, a second-site compensatory mutation in a distal CA domain was selected that rescues the virus to a CsA-independent phenotype . This study parallels our work on the evolution of a T20-independent variant .
In a recent 2006 study, Adamson et al reported a partial drug-dependence phenotype for HIV-1 variants that became resistant to the PA-457 (beviramat) inhibitor . This drug blocks a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of CA. Similar to our report on T20-dependence, they show that drug-resistant variants with a single resistance mutation had diminished replication capacity and second-site compensatory mutations were able to rescue virus replication. Thus, the first resistance mutation sets the stage for the second compensatory change that integrates the drug in the mechanistic process.