Figure 3

Human retroviruses subvert autophagy. (A) HIV-1 infection of macrophages induces autophagy to enhance viral replication. Inhibition of autophagy by 3-MA, Beclin-1 siRNA, Atg7 siRNA and vitamin D has been demonstrated to reduce HIV-1 replication [125, 126, 128]. Additionally, HIV-1 Nef protein inhibits autophagic clearance of HIV-1 by blocking the autophagosome-lysosome fusion; treatment of vitamin D overcomes this blocking to enhance HIV-1 clearance [128]. (B) The autophagic effect of HIV-1 infection in CD4⁺ T cells is still controversial. Espert et al. and Zhou et al. observed that HIV-1-infected CD4⁺ T cells exhibits reduced autophagy [127, 129]. However, Wang et al. reported that HIV-1 infection of CD4⁺ T cells activates autophagy and that treatment of autophagy inhibitor 3-MA and Beclin-1 siRNA suppresses HIV-1 replication [131]. Eekels et al. performed shRNA-mediated stable knockdown of autophagy-related genes (such as Atg5 and Atg16) and showed an inhibitory effect on HIV-1 production [132]. In uninfected bystander CD4⁺ T cells, circulating HIV-1 env protein activates autophagy to cause apoptotic cell death, which can be inhibited by treatment of 3-MA and BFA or Beclin-1 siRNA and Atg7 siRNA [127, 133, 134]. (C) HTLV-1-infected T cells exhibit an increase of autophagy for its survival and viral replication [147] (Tang et al., submitted). Genetic disruption of Beclin-1 reduces the viability of HTLV-1-transformed T cells [147], and BFA treatment enhances HTLV-1 replication (Tang et al., submitted). HTLV-2 Tax-immortalized CD4⁺ T cells show increased autophagy, which is essential for its survival. Autophagy inhibitors 3-MA and chloroquine suppress the proliferation and induce the apoptosis of HTLV-2 Tax-immortalized T cells [148]