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Innate immune responses represent the first line of defense against invading microbes including HIV-1. Macrophages and other myeloid cell populations mediate responses to viruses, bacteria and fungi in a rapid, non-specific manner following binding of moieties from these pathogens to innate immune receptors. Macrophages express several types of innate immune receptors called “pattern recognition receptors” that bind distinct pathogen-associated molecular patterns. Chief among the innate immune receptors in macrophages are a family of receptors called the Toll-like receptors that reside on the plasma membrane as well as within endosomal vesicles. The binding of ligand to Toll-like receptors and other types of innate immune receptors triggers a down-stream signaling cascade designed to rapidly induce expression of inflammatory mediators and innate immune molecules to thwart infection. Several nucleic acid based approaches have been developed to block or eliminate HIV-1 infection of macrophages and other myeloid cells, including the use of short-interfering RNA to block viral and cellular protein expression, and more recently, genomic engineering with CRISPR/Cas to cleave viral or cellular genes important in HIV-1 infection and replication. However, because these constructs are comprised of nucleic acids, they function as powerful ligands to activate select innate immune receptors, triggering anti-viral responses that effectively inhibit HIV-1 infection. This review will summarize the potential dual-benefits of nucleic acid-based therapies to block HIV-1 infection of macrophages.