Researchers identify targeting of the lncRNA SAF as a potential means to specifically induce cell death in HIV-1-infected macrophages

Long noncoding RNAs (lncRNAs) impart significant regulatory functions in a diverse array of biological pathways and manipulation of these RNAs provides an important avenue to modulate such pathways, particularly in disease. Our knowledge about lncRNAs’ role in determination of cellular fate during HIV-1 infection remains sparse. Here, Cornell University researchers have identified the impact of the lncRNA SAF in regulating apoptotic effector caspases in macrophages, a long-lived cellular reservoir of HIV-1, that are largely immune to virus-induced cell death. Expression of SAF is significantly up-regulated in HIV-1-infected human monocyte-derived macrophages (MDM) compared with bystander and virus-nonexposed cells. A similar enhancement in SAF RNA expression is also detected in the HIV-1-infected airway macrophages obtained by bronchoalveolar lavage of HIV-1-infected individuals. Down-regulation of SAF with siRNA treatment increases caspase-3/7 activity levels in virus-infected MDMs. This induction of apoptotic caspases occurs exclusively in HIV-1-infected macrophages and not in bystander cells, leading to a significant reduction in HIV-1 replication and overall viral burden in the macrophage culture. This study identifies targeting of the lncRNA SAF as a potential means to specifically induce cell death in HIV-1-infected macrophages.

lncRNA SAF expression in HIV-1–infected MDMs

lncrna

(A) Venn diagram summarizing changes in lncRNA expression profile in HIV-1–infected and bystander cells compared with virus-nonexposed MDMs. At least twofold up- or down-regulation compared with nonexposed MDMs was considered as a change in expression. (B) A summary of the relative expressions of the 16 lncRNAs that were differentially expressed in HIV-1–infected (red dot) MDMs compared with bystander (blue box) cells. The lncRNA SAF is identified with a box. (C) Fold changes (mean ± SEM) in expression of the lncRNA SAF were determined by qRT-PCR in nonexposed, bystander, and virus-infected MDMs (n = 4). Significance of difference among groups determined by one-way ANOVA is indicated above the groups, *P < 0.05.

Boliar S, Gludish DW, Jambo KC, Kamng’ona R, Mvaya L, Mwandumba H, Russell DG. (2019) Inhibition of the lncRNA SAF drives activation of apoptotic effector caspases in HIV-1-infected human macrophages. Proc Natl Acad Sci USA 16(15):7431-7438. [article]

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