Susceptibility and adaptation to human TRIM5α alleles at positive selected sites in HIV-1 capsid

- HIV-1 capsid, the target of TRIM5α, is highly conserved.
- A limited number of residues in capsid are under positive selective pressure.
- Mutation at these sites does not result in escape from modest effects of TRIM5α.
- Some minor frequency alleles lead to greater susceptibility to TRIM5α restriction.
- HIV-1 capsid represents an optimum of adaptation to human TRIM5α.

Numerous in vitro studies attribute to human TRIM5α some modest anti-HIV-1 activity and human population studies suggest some differential effect of TRIM5α polymorphisms on disease progression. If the activity of TRIM5α were relevant in vivo, it could result in positive selection on the viral capsid. To address this issue, we identified 10 positively selected sites in HIV-1 capsid from multiple viral strains and generated 17 clade B viruses carrying a minor (i.e. low frequency) residue or an alanine at those positions. All recombinant viruses were susceptible to the modest effect of common human TRIM5α and allelic variants R136Q, and H419Y; H43Y and G249D TRIM5α were generally inactive. Increased sensitivity to TRIM5α was observed for some capsid variants, suggesting that minor residues are selected against in human populations. On the other hand, the modest potency of human TRIM5α does not translate in escape mutations in the viral capsid.