Galectin-3 promotes caspase-independent cell death of HIV-1-infected macrophages

HIV-1-infected macrophages are a key contributor to the formation of a viral reservoir and new treatment strategies focus on eliminating this pool of virus. Galectin-3 is a potent apoptosis-inducing protein that regulates diverse cellular activities. In the present study, we investigated whether galectin-3 could induce cell death in HIV-1-infected macrophages using HIV-1-infected THP1 monocytes (THP1-MNs) and THP1-derived macrophages (THP1-MΦs) as in vitro cellular models. We found that THP1-MΦs were more resistant than the THP1-MNs to HIV-1 infection-induced death, and that HIV-1 infection of the THP1-MΦs increased expression of the anti-apoptotic proteins Mcl-1, Bcl-2 and Bcl-xL. Additionally, galectin-3 but not FasL, tumor necrosis factor (TNF)-related apoptosis-inducing ligand or TNF-α, could induce cell death in HIV-1-infected THP1-MΦs. A similar result was shown for primary human monocyte-derived macrophages. Galectin-3-induced cell death was also significantly increased in macrophages obtained from SIVmac251-infected macaques compared to that of macrophages from healthy macaques. Furthermore, galectin-3-induced cell death in HIV-1-infected THP1-MΦs was caspase independent. Interestingly, endonuclease G (Endo G) was increased in the nucleus and decreased in the cytoplasm of galectin-3-treated cells; thus, galectin-3-induced cell death in HIV-1-infected THP1-MΦs is most likely related to the translocation of Endo G from the cytoplasm to the nucleus. These findings suggest that galectin-3 may potentially aid in the eradication of HIV-1/SIV-infected macrophages.