Abstract
ALG-2 interacting protein X (ALIX) links HIV-1 Gag to the components of ESCRT-III. HIV-1 engages the ALIX via its nucleocapsid and LYPXnL motif in p6. Overexpression of ALIX corrects the release defect of PTAP deleted HIV-1 via LYPXnL/ALIX pathway. However, HIV-1 subtype C lacks the LYPXnL motif and hence cannot employ LYPXnL/ALIX mechanism. Though the preferential occurrences of PYXE insertion in HIV-1 C p6 is predicted to restore the ALIX binding site there is no functional proof to support these observations. In this study we show that HIV-1 construct with subtype C p6 having PTAP deletion and PYRE insertion (pNL-INp6ΔPTAP/PYRE) could respond to ALIX overexpression. Notably, conserved Phenyl alanine residue (F676) in ALIX was critical for ALIX mediated release of pNL-INp6ΔPTAP/PYRE implying the critical role of this hydrophobic patch in ALIX recruitment. In addition, we show that Nedd4-1 could also correct the release defect of pNL-INp6ΔPTAP/PYRE. Moreover, Nedd4-1 was more robust compared to ALIX in its ability to stimulate the release of pNL-INp6ΔPTAP/PYRE. Replication kinetic data highlights the positive effect of PYRE insertion on virus replication. In summary, our data reveals the functional role of PYRE insertion towards the cooperative mechanism of ALIX/Nedd4-1 in virus release in the absence of PTAP/Tsg101 pathway.
Highlights
HIV-1 Gag harbours a short 52 amino acid peptide p6 at its C-terminus that plays a vital role in virus release form host cell membrane
In a study published by our group, we had reported that pNL4.3 carrying PTAP deleted subtype C p6 could not respond to the ALG-2 interacting protein X (ALIX) overexpression[16]
In our previous study we have reported that the natural deletion of L35Y36 in p6 gag eliminates the LYPXnL/ALIX auxiliary release pathway in HIV-1 subtype C16
Summary
HIV-1 Gag harbours a short 52 amino acid peptide p6 at its C-terminus that plays a vital role in virus release form host cell membrane. Mutations in the LYPXnL motif abrogate the interaction between HIV-1 p6 Gag and ALIX V domain[12,13,14]. PYXE insertion in HIV-1 subtype C introduces the stretch of a sequence similar to ALIX binding motif characterized in SIVmac[239]. While HIV-1 subtype C lacks consensus LYPXnL motif and PYXE insertion introduces the elements similar to the type 3 ALIX binding motif in HIV-1 C p6, we wondered www.nature.com/scientificreports/. PYRE insertion in HIV-1 subtype C P6 incorporates the amino acid residues similar to type 3 ALIX binding motif. In present study we have used the PYRE, a variant of PYXE to investigate its role towards ALIX mediated release in HIV-1 subtype C
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