The type 1
interferon-regulated
E3 ubiquitin ligase MARCH1 reduces surface expression of HIV-1 envelope
glycoproteins (Env) and their packaging into nascent virions, a condition that restricts viral infectivity. However, how HIV-1 counters this restriction, notably during
infection of macrophages, remains unclear. Here, we show that the HIV-1 accessory
protein Vpu increases the levels of microRNAs-25 and -93 to target MARCH1
mRNA. By recruiting β-TRCP, a component of the SCFβ-TRCP
E3 ligase complex that targets phosphorylated β-
catenin for degradation, Vpu increases β-
catenin levels, which, in concert with TCF4/LEF, drives transcription of the MARCH1-targeting
microRNAs. This potentiates HIV-1 infectivity as a result of increased Env incorporation into nascent virions. Pharmacological targeting of the β-
catenin pathway inhibits Vpu-mediated upregulation of microRNAs-25 and -93 and restores MARCH1 restriction on HIV-1 infectivity. Overall, our findings highlight a novel mechanism by which HIV-1 counteracts MARCH1 by downregulating its expression via Vpu-mediated induction of microRNAs-25 and -93. IMPORTANCE In order to efficiently produce infectious viral particles, HIV must counter several restrictions exerted by host cell
antiviral proteins. MARCH1 is a member of the MARCH
protein family that restricts
HIV infection by limiting the incorporation of
viral envelope glycoproteins into nascent virions. Here, we identified two regulatory RNAs, microRNAs-25 and -93, induced by the HIV-1 accessory
protein Vpu, that downregulate MARCH1
mRNA. We also show that Vpu induces these cellular
microRNAs in macrophages by hijacking the cellular β-
catenin pathway. The notion that HIV-1 has evolved a mechanism to counteract MARCH1 restriction on viral infectivity underlines the importance of MARCH1 in the host
antiviral response.