Determinants of cyclophilin A-dependent TRIM5 alpha restriction against HIV-1

TRIM5 alpha is a host protein that can bind to incoming retroviral capsid (CA) and inhibit retroviruses in a species-specific manner. The CA protein of HIV-1 also interacts with high affinity to the host protein cyclophilin A (CypA). This binding has been shown to positively affect some early stage of the viral life cycle in human cells. However, the CypA/CA interaction also renders HIV-1 more susceptible to rhesus TRIM5 alpha (rhTRIM5 alpha) restriction. We find that the ability of old world monkey TRIM5 alpha genes to restrict HIV-1 in a CypA-dependent manner is widespread. On the other hand, we find that simian immunodeficiency viruses from tantalus monkeys (SIVagmTAN), is unlike HIV-1 in that CypA does not enhance the rhTRIM5 alpha restriction against the virus even though the CA of this virus, like HIV-1, does bind CypA. Mapping of the determinants for this phenotype by swapping regions on CA between SIVagmTAN and HIV-1 showed that when SIVagmTAN contains loops between helices 4/5 (4-5 loop) and 6/7 (6-7 loop) from HIV-1 CA, it becomes susceptible to the CypA-enhanced rhTRIM5 alpha restriction. Surprisingly, when SIVagmTAN contains either loop from HIV-1 CA, it gains sensitivity to TRIM5 alpha from species which originally have no effect on the wild-type virus. Moreover, we find that CypA/CA interaction occurs early after viral entry but the CypA-enhanced restriction mostly acts on the stage after reverse transcription.