HIV-2 glycoproteins upregulate microRNAs 25 and 93 to counter the MARCH1 antiviral effect in macrophages

The membrane-associated E3 ubiquitin ligase MARCH1 restricts HIV-1 infectivity by decreasing the amount of cell surface Env glycoproteins and their incorporation into progeny virions. To circumvent this restriction, the HIV-1 accessory protein Vpu increases the levels of microRNAs 25 and 93 that target MARCH1 RNA. Mechanistically, Vpu interaction with the β-TrCP substrate receptor of the SCF^β-TrCP E3 ligase, a host partner critical for Vpu functions, leads to a stabilization of SCF^β-TrCP cellular targets, such as β-catenin, which drives transcription of the MARCH1-targeting microRNAs. Here, we show that HIV-2 and SIVmac239, which do not encode for Vpu, also upregulate microRNAs 25 and 93 in macrophages, as well as in the macrophage-like THP-1 cell line model. Inhibiting the MARCH1 mRNA-targeting microRNAs impaired HIV-2 infectivity and reduced viral spread in macrophages. While none of the HIV-2 accessory proteins upregulated microRNAs 25 and 93, the Env glycoproteins of HIV-2 and SIVmac239 were sufficient to induce their expression. Depletion of β-TrCP-1 and 2 or pharmacological inhibition of β-catenin in THP-1 cells revealed that Env-mediated upregulation of microRNA 25 and 93 is β-TrCP dependent and involves β-catenin, similar to Vpu. Our findings highlight a new function of the HIV-2 and SIVmac239 glycoproteins as inducers of microRNAs 25 and 93 that counteract MARCH1 and potentiate viral replication in macrophages.

Macrophage infection by primate lentiviruses (HIV-1, HIV-2, and SIV) is restricted by, among other host factors, the MARCH1 membrane-associated protein. HIV-1 circumvents the MARCH1 restriction by using its accessory protein Vpu, which induces the anti-MARCH1 microRNAs 25 and 93. HIV-2 has infected up to 2 million people so far, and SIV infection is indispensable for animal models of primate lentivirus pathogenesis. These two lentiviruses do not have a vpu gene, but also target MARCH1 by inducing the same microRNAs. We have now determined that the HIV-2 and SIV antagonists of MARCH1 are their envelope glycoproteins. The HIV-2 and SIVmac239 Env glycoproteins upregulate microRNAs 25 and 93 by disrupting the β-catenin pathway, similar to HIV-1 Vpu. The fact that different lentiviruses have developed a similar strategy using microRNAs to counter MARCH1 antiviral activity emphasizes its relevance in the antiviral host response, as well as a target in antiviral therapy.