Proteasome inhibitors uncouple rhesus TRIM5α restriction of HIV-1 reverse transcription and infection

The primate TRIM5 alpha proteins have recently been defined as cellular restriction factors, preventing primate infection by retroviruses from different species. For instance, rhesus TRIM5 alpha (rhTRIM5 alpha) restricts infection by HIV-1. Virtually all TRIM5a proteins block the early replication of retroviruses by preventing the accumulation of reverse transcription products, but the underlying mechanism remains unclear. In this article, we find that disrupting proteasome function alters rhTRIM5 alpha localization and allows the normal generation of HIV-1 late reverse transcription products, even though HIV-1 infection and the generation of nuclear 1-LTR and 2-LTR viral cDNA forms remain impaired. This finding suggests rhTRIM5 alpha restricts HIV infection in two distinct phases: (i) altering the normal passage of the reverse-transcribing viral genome to the nucleus and (ii) targeting the reverse transcription complex to be disrupted by the proteasome. Because proteasome inhibitor blocks the second phase, accumulation of a nonfunctional viral DNA genome can be readily observed. Defining each phase may reveal HIV-1 targets for future antiviral therapy in which dual blockade may be equally as effective as naturally occurring rhTRIM5 alpha protein in preventing HIV-1 infection in vivo.