Commentary: MARCH8 Inhibits HIV-1 Infection by Reducing Virion Incorporation of Envelope Glycoproteins

Recently, Kenzo Tokunaga's group reported a novel restriction factor against HIV, MARCH8, which is highly expressed in terminally differentiated myeloid cells such as macrophages. Virus infection in macrophages was first observed in HIV-infected patients in the mid-1980s (Gyorkey et al., 1985; Ho et al., 1986; Koenig et al., 1986). Three decades have passed since then; however, the role of HIV-infected macrophages in AIDS pathogenesis remains controversial. Here, some potential implications of Tokunaga et al.'s study on this controversy will be addressed. SIV-infected rhesus monkeys are a good model for investigating the role of HIV-infected macrophages because their pathology resembles the slow progression of AIDS in humans. A comparative study of rhesus macaques infected with T cell-tropic SIVmac239 (Kestler et al., 1990) or with macrophage-tropic SIVmac316 (Mori et al., 1992), which carries nine mutations compared with SIVmac239 (Johnson et al., 2003) found that SIVmac316 replicates with the simian body as well as SIVmac239 just after inoculation. However, SIVmac316 induces a slower disease progression than SIVmac239, demonstrating that the contribution of virus-infected macrophages to pathogenesis is smaller than that of virus-infected T cells. Studies have also used an SIV that lacks expression of its accessory protein, Vpx, which is critical for SIV/HIV-2 replication in macrophages and resting T lymphocytes and is also important in activated T lymphocytes (Fujita et al., 2010, 2012; Baldauf et al., 2012). Rhesus macaques infected with a vpx-deleted SIVmac239 eventually died after a slower disease progression than that of animals infected with wild-type SIVmac239 (Westmoreland et al., 2014). In monkeys infected with vpx-deleted SIVmac239, minimal macrophage infection was detected, even though infected macrophages were observed following wild-type SIV infection. Furthermore, there was a recent study of rhesus macaques infected with SIVmac239 or SIVmac316 mutants, both of which had mutations in Vpx inhibiting the ability of this protein to confer infectivity. The viruses that recovered their replication ability in this study only appeared in the animals infected with the T cell-tropic SIVmac239, demonstrating the lower importance of virus replication in macrophages than that in T cells (Shingai et al., 2015). Based on these results, it is likely that HIV has difficulty replicating in macrophages in vivo and that HIV-infected macrophages play a minimal role in progressing the general symptom of AIDS. Although HIV-infected macrophages are not critical for disease progression, their role in HIV infection may be to serve as an HIV reservoir in the body, acting as an …