HIV-2 glycoproteins upregulate microRNAs 25 and 93 to counter the MARCH1 antiviral effect 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 <i>vpu</i> 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.