The cyclophilin A-binding loop of the capsid regulates the human TRIM5α sensitivity of nonpandemic HIV-1.

The rather few cases of humans infected by HIV-1 N, O, or P raise the question of their incomplete adaptation to humans. We hypothesized that early postentry restrictions may be relevant for the impaired spread of these HIVs. One of the best-characterized species-specific restriction factors is TRIM5α. HIV-1 M can escape human (hu) TRIM5α restriction by binding cyclophilin A (CYPA, also known as PPIA, peptidylprolyl isomerase A) to the so-called CYPA-binding loop of its capsid protein. How non-M HIV-1s interact with huTRIM5α is ill-defined. By testing full-length reporter viruses (Δ env ) of HIV-1 N, O, P, and SIVgor (simian IV of gorillas), we found that in contrast to HIV-1 M, the nonpandemic HIVs and SIVgor showed restriction by huTRIM5α. Work to identify capsid residues that mediate susceptibility to huTRIM5α revealed that residue 88 in the capsid CYPA-binding loop was important for such differences. There, HIV-1 M uses alanine to resist, while non-M HIV-1s have either valine or methionine, which avail them for huTRIM5α. Capsid residue 88 determines the sensitivity to TRIM5α in an unknown way. Molecular simulations indicated that capsid residue 88 can affect trans -to- cis isomerization patterns on the capsids of the viruses we tested. These differential CYPA usages by pandemic and nonpandemic HIV-1 suggest that the enzymatic activity of CYPA on the viral core might be important for its protective function against huTRIM5α.
Competing Interests: Competing interests statement:The authors declare no competing interest.