Analysis of human immunodeficiency virus type 1 containing HERV-K protease

The human endogenous retrovirus, type K (HERV-K) represents the most biolog ically active form of known retroelements present in the human genome. Seve ral HERV-K genomes have transcriptionally active open reading frames and en code their own protease (PR). The HERV-K PR has been shown to authentically cleave human immunodeficiency virus type 1 (HIV-1) matrix-capsid peptide i n the presence of HIV-1 PR inhibitors. This raised the possibility that HER V-K PR could complement HIV-1 PR function in HIV-1-infected individuals. To investigate this possibility, we fused the HIV-1 vpr gene to the HERV-K PR gene (vpr-PR). The vpr-PR expression plasmid and a PR-defective HIV-1 clon e were cotransfected into 293T cells. Progeny virions were assayed for proc essing of the HIV-1 polyproteins by Western blot and for changes in infecti vity. HERV-K PR fused to Vpr was incorporated into HIV-1 virions at a high concentration and cleaved the Gag and Pol precursor proteins. However, neit her Gag nor Pol polyproteins were correctly processed. Moreover, the HERV-K PR did not restore virus infectivity. While these results do not exclude t he possibility that the HERV-K PR could complement an HIV-1 PR whose functi on is impaired due to drugs or drug-resistant mutations, they clearly demon strate that the HERV-K PR cannot substitute for the function of the wild-ty pe HIV-1 PR.