Background:  Primate cells contain innate intracellular factors that restrict HIV-1 infection by targeting the incoming viral capsid core. Recognition of the capsid core by restriction factors blocks HIV-1 replication at a post-entry step prior to integration. The fact that host cells have evolved effective mechanisms to inhibit HIV-1 replication at this step suggests a point of vulnerability in the retroviral life cycle. To escape this restriction, HIV-1 recruits host cyclophilin A (CypA) forming potentially a protective shield. Supporting this notion, abrogation of CypA-capsid interactions impairs HIV-1 infectivity. In this study, we asked if acquisition of CypA is the unique mechanism of defense against these restriction factors or if HIV-1 exploits additional stratagems to ensure its survival in the host.

Methods:  Using a novel nonimmunosuppressive cyclosporine A analog, Debio-025, which disrupts CypA-capsid interactions, we screened for HIV-1 isolates that do not depend on CypA-capsid interactions for replication in human cells.

Results:  We found that a subset of HIV-1 primary isolates from the main group replicates in human cells even in the presence of Debio-025, suggesting that although a majority of HIV-1 isolates depend on CypA-capsid interactions to infect human cells, viral variants spontaneously occur that have the capacity to escape human restriction in a CypA-independent manner. We identified a capsid motif that governs CypA-independent resistance of HIV-1. This motif renders HIV-1 infectivity superior to that observed in wild type virus, suggesting that CypA-mediated protection is not optimal. This motif also renders HIV-1 more competent to infect nonhuman primate species, which normally restrict HIV-1, suggesting a universal mechanism of defense against primate restriction.

Conclusions:  We found that HIV-1 exploits at least 2 strategies to escape restrictions in human cells. One defensive strategy consists of the recruitment of CypA onto its viral capsid core that is thought to protect the core from attack by restriction factors. The second defensive strategy relies on the preexistence of a capsid motif, which renders the viral capsid core resistant or invisible to restriction factors. In contrast to the CypA-mediated defense strategy above, this strategy does not rely on CypA-capsid interactions, suggesting that HIV-1 exploits CypA-dependent and -independent defensive strategies to guarantee successful colonization of primates.

Keywords: HIV; Restriction Factor; Cyclophilin A