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.
From the Department of Clinical Viro Immunology, Sanquin Research, Landsteiner Laboratory, and Center of Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
Received 16 May, 2007
Revised 3 July, 2007
Accepted 10 July, 2007
Correspondence to NA Kootstra, Department of Clinical Viro Immunology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. Tel: +31 20 12 3317; fax: +31 20 512 3310; e-mail: N.Kootstra@sanquin.nl