The presence of the Trim5alpha escape mutation H87Q in the capsid of late stage HIV-1 variants is preceded by a prolonged asymptomatic infection phase.

BACKGROUND: Recently, the tripartite interaction motif 5alpha (Trim5alpha) has been identified as an inhibitory factor blocking infection of a broad range of retroviruses in a species-specific manner. In particular, HIV-1 replication can be efficiently blocked by Trim5alpha from Old World monkeys. The cyclophilin A binding region in the HIV-1 capsid is believed to be the viral determinant for Trim5alpha, and mutations in this region lift the restriction in simian cells. Human Trim5alpha is also able to inhibit HIV-1 replication in vitro, implying that Trim5alpha may contribute to host control of HIV-1 replication in vivo.
METHODS: HIV-1 variants from participants of the Amsterdam cohort studies were analysed for Trim5alpha escape mutations in the capsid. Patients who harboured HIV-1 variants with Trim5alpha escape mutations were compared with patients who lacked such variants in terms of clinical course of infection.
RESULTS: Trim5alpha escape mutants emerged in the late phase of infection and were ultimately present in 13.7% of HIV-1 infected individuals. Patients who developed Trim5alpha escape variants late in infection had a significantly lower set-point plasma viral RNA load and concomitantly a prolonged asymptomatic survival as compared to individuals who lacked Trim5alpha escape mutants. This protective effect was stronger in individuals who later developed X4 variants. In addition, X4-emergence was delayed in individuals who later developed Trim5alpha escape variants, compatible with suppression of viral replication.
CONCLUSION: Our data are compatible with Trim5alpha-mediated suppression of viral replication, resulting in prolonged asymptomatic survival and ultimately the selection of Trim5alpha escape variants.