HIV-1 promotes ubiquitination of the amyloidogenic C-terminal fragment of APP to support viral replication

HIV-1 replication in macrophages and microglia involves intracellular assembly and budding into modified subsets of multivesicular bodies (MVBs), which support both viral persistence and spread. However, the cellular factors that regulate HIV-1's vesicular replication remain poorly understood. Recently, amyloid precursor protein (APP) was identified as an inhibitor of HIV-1 replication in macrophages and microglia via an unknown mechanism. Here, we show that entry of HIV-1 Gag into MVBs is blocked by the amyloidogenic C-terminal fragment of APP, C99, but not by the non-amyloidogenic product, C83. To counter this, Gag promotes multi-site ubiquitination of C99 which controls both exocytic sorting of MVBs and further processing of C99 into toxic amyloids. Processing of C99, entry of Gag into MVBs and release of infectious virus could be suppressed by expressing ubiquitination-defective C99 or by & gamma;-secretase inhibitor treatment, suggesting that APP's amyloidogenic pathway functions to sense and suppress HIV-1 replication in macrophages and microglia. Amyloid precursor protein has been identified as an inhibitor of HIV-1 replication. Here, Gu et al further characterise the details and impact of this interaction on HIV replication in myeloid cells that contribute to neurological disease.

Automated summary

Amyloid precursor protein (APP) inhibits HIV-1 replication in macrophages and microglia by blocking HIV-1 Gag entry into multivesicular bodies (MVBs). This blockage is specifically caused by the amyloidogenic C-terminal fragment of APP, C99, and is not observed with the non-amyloidogenic product C83. Gag counters this blockage by promoting multi-site ubiquitination of C99, which regulates exocytic sorting of MVBs and further processing of C99 into toxic amyloids.