Solving the Paradox: Deciphering HIV-I Persistence in Hematopoietic Stem

Opposing the common interferon-stimulated antiviral mechanisms employed by terminally differentiated cells, a recent study revealed that stem cells constitutively express critical subsets of interferon stimulated genes (ISGs) that confer effective protection against viral infection. Three members of the Interferon-induced Transmembrane (IFITM) protein family, IFITM 1, 2, and 3 have known anti-HIV-1 activities, and were found intrinsically expressed in various stem cell types including the hematopoietic stem cells. Interestingly, strong evidence reported recently indicates that the multipotent hematopoietic stem and progenitor cells (HSPCs) could serve as an HIV-1 reservoir which harbours latent, clonal and functional HIV-1 proviral genomes in anti-retroviral therapy-treated patients. This observation then prompts the apparent paradox: how does HIV-1 establish functional proviral reservoirs in HSPCs in the presence of a potent and constitutive expression of the antiviral IFITM proteins? Based on available literature, this study attempts to elucidate the paradox by summarizing reported anti-HIV-1 ISGs expressed intrinsically in hematopoetic stem cells (HSCs), outlining a model for HIV-1 reservoir establishment in HSCs in the context of IFITMs, and finally proposing an IFITM-based therapeutic strategy against HIV-1 transmission.