These results suggest that adamantylGb3 may provide a new basis for blocking HIV infections, irrespective of HIV envelope/chemokine co-receptor preference or resistance to other therapeutics.

Several human histo-blood groups are glycosphingolipids, including P/P1/P k . Glycosphingolipids are implicated in HIVhost-cell-fusion and some bind to HIVgp120 in vitro. Based on our previous studies on Fabry disease, where P k accumulates and reduces infection, and a soluble P k analog that inhibits infection, we investigated cell surface-expressed P k in HIV infection. HIV-1 infection of peripheral blood-derived mononuclear cells (PBMCs) from otherwise healthy persons, with blood group P 1 k , where P k is overexpressed, or blood group p, that completely lacks P k , were compared with draw date-matched controls. Fluorescenceactivated cell sorter analysis and/or thin layer chromatography were used to verify P k levels. P 1 k PBMCs were highly resistant to R5 and X4 HIV-1 infection. In contrast, p PBMCs showed 10-to 1000-fold increased susceptibility to HIV-1 infection. Surface and total cell expression of P k , but not CD4 or chemokine coreceptor expression, correlated with infection. P k liposome-fused cells and CD4 ؉ HeLa cells manipulated to express high or low P k levels confirmed a protective effect of P k . We conclude that P k expression strongly influences susceptibility to HIV-1 infection, which implicates P k as a new endogenous cell-surface factor that may provide protection against HIV-1 infection. (Blood. 2009;113:4980-4991)

Control of RNA processing plays a major role in HIV-1 gene expression. To explore the role of several hnRNP proteins in this process, we carried out a siRNA screen to examine the effect of depletion of hnRNPs A1, A2, D, H, I and K on HIV-1 gene expression. While loss of hnRNPs H, I or K had little effect, depletion of A1 and A2 increased expression of viral structural proteins. In contrast, reduced hnRNP D expression decreased synthesis of HIV-1 Gag and Env. Loss of hnRNP D induced no changes in viral RNA abundance but reduced the accumulation of HIV-1 unspliced and singly spliced RNAs in the cytoplasm. Subsequent analyses determined that hnRNP D underwent relocalization to the cytoplasm upon HIV-1 infection and was associated with Gag protein. Screening of the four isoforms of hnRNP D determined that, upon overexpression, they had differential effects on HIV-1 Gag expression, p45 and p42 isoforms increased viral Gag synthesis while p40 and p37 suppressed it. The differential effect of hnRNP D isoforms on HIV-1 expression suggests that their relative abundance could contribute to the permissiveness of cell types to replicate the virus, a hypothesis subsequently confirmed by selective depletion of p45 and p42.