The presence of the Trim5α escape mutation H87Q in the capsid of late stage HIV-1 variants is preceded by a prolonged asymptomatic infection phase

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Abstract
Background: Recently, the tripartite interaction motif 5α (Trim5α) 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 Trim5α from Old World monkeys. The cyclophilin A binding region in the HIV-1 capsid is believed to be the viral determinant for Trim5α, and mutations in this region lift the restriction in simian cells. Human Trim5α is also able to inhibit HIV-1 replication in vitro, implying that Trim5α 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 Trim5α escape mutations in the capsid. Patients who harboured HIV-1 variants with Trim5α escape mutations were compared with patients who lacked such variants in terms of clinical course of infection. Results: Trim5α escape mutants emerged in the late phase of infection and were ultimately present in 13.7% of HIV-1 infected individuals. Patients who developed Trim5α 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 Trim5α 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 Trim5α escape variants, compatible with suppression of viral replication. Conclusion: Our data are compatible with Trim5α-mediated suppression of viral replication, resulting in prolonged asymptomatic survival and ultimately the selection of Trim5α escape variants.