Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression.

Area of Science:

• Molecular Biology
• Structural Biology
• Virology

Background:

• Human endogenous retrovirus type K (HERV-K) expression is implicated in cancers and neurodegenerative diseases.
• HERV-K mRNA nuclear export relies on the RcRE RNA element and Rec protein, analogous to HIV-1's RRE-Rev system.
• HIV-1 Rev protein can enhance HERV-K mRNA export, increasing HERV-K expression in HIV-infected individuals.

Purpose of the Study:

• To elucidate the structural basis of the interaction between HIV-1 Rev and the HERV-K RcRE RNA.
• To understand the mechanism of HERV-K mRNA nuclear export and its regulation by HIV-1 Rev.

Main Methods:

• Small-angle X-ray scattering (SAXS) was used to determine the solution conformation of the RcRE RNA.
• Atomic force microscopy (AFM) visualized RcRE RNA conformations.
• Deletion variants were analyzed using SAXS and biochemical assays to assess the importance of RcRE structure.

Main Results:

• The HERV-K RcRE RNA (433 nt) can adopt folded or extended conformations.
• SAXS analysis revealed a conserved 'A'-shaped topological structure for a truncated RcRE, similar to HIV-1 RRE.
• This 'A' shape is crucial for efficient Rev-RcRE complex formation and nuclear export activity.

Conclusions:

• The study provides the first 3D topological structure of a HERV RNA element, the RcRE.
• The RcRE's 'A'-shaped structure is essential for its recognition by HIV-1 Rev, explaining elevated HERV-K expression in HIV patients.
• These findings offer structural insights into HERV-K regulation and its modulation by HIV-1 infection.