Abstract
As part of the Pr55Gag polyprotein, p6 fulfills an essential role in the late steps of the replication cycle. However, almost nothing is known about the functions of the mature HIV-1 p6 protein. Recently, we showed that p6 is a bona fide substrate of the insulin-degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease. This phenomenon appears to be specific for HIV-1, since p6 homologs of HIV-2, SIV and EIAV were IDE-insensitive. Furthermore, abrogation of the IDE-mediated degradation of p6 reduces the replication capacity of HIV-1 in an Env-dependent manner. However, it remained unclear to which extent the IDE mediated degradation is phylogenetically conserved among HIV-1. Here, we describe two HIV-1 isolates with IDE resistant p6 proteins. Sequence comparison allowed deducing one single amino acid regulating IDE sensitivity of p6. Exchanging the N-terminal leucine residue of p6 derived from the IDE sensitive isolate HIV-1NL4-3 with proline enhances its stability, while replacing Pro-1 of p6 from the IDE insensitive isolate SG3 with leucine restores susceptibility towards IDE. Phylogenetic analyses of this natural polymorphism revealed that the N-terminal leucine is characteristic for p6 derived from HIV-1 group M except for subtype A, which predominantly expresses p6 with an N-terminal proline. Consequently, p6 peptides derived from subtype A are not degraded by IDE. Thus, IDE mediated degradation of p6 is specific for HIV-1 group M isolates and not occasionally distributed among HIV-1.
Highlights
Within Gag, the HIV-1 p6 protein is synthesized as the C-terminal domain [1]
insulin-degrading enzyme (IDE)-mediated degradation was phylogenetically formed alongside the leucine residue at position one of p6, which is characteristic for most non-A subtypes of HIV-1 group M
Stabilization by an N-Terminal Proline Renders HIV-1 Replication Resistant to Treatment with an Previously, we reported that stabilization of p6 via triplication of the PTAP motif results in reduced replication capacity of X4 tropic HIV-1 in PBMC
Summary
Within Gag, the HIV-1 p6 protein is synthesized as the C-terminal domain [1]. It consists of only 52 amino acids (aa), thereby belonging to the smallest lentiviral proteins. We describe two HIV-1 isolates that contain IDE-insensitive p6 variants Sequence comparison of those p6 proteins allowed us to deduce one single aa substitution that impairs degradation of p6 by IDE, namely proline-1 (Pro-1) at the N-terminus of p6. The HIV-1 p6 L1P mutant mostly behaves like previously described IDE insensitive p6 mutants regarding virus release, Gag processing to p24 and replication capacity. This particular N-terminal aa grants insight in the phylogenetic background and the extent of the p6 IDE interaction in HIV-1. IDE-mediated degradation was phylogenetically formed alongside the leucine residue at position one of p6, which is characteristic for most non-A subtypes of HIV-1 group M
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