SAMHD1 is a host restriction factor for human immunodeficiency virus 1 (HIV‐1) in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi‐Goutières syndrome and are found in cancers including chronic lymphocytic leukaemia. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of deoxynucleoside triphosphates, thereby preventing reverse transcription of retroviral genomes. However, in vivo evidence for SAMHD1's antiviral activity has been lacking. We generated Samhd1 null mice that do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1 −/− cells have elevated deoxynucleoside triphosphate (dNTP) levels but, surprisingly, SAMHD1 deficiency did not lead to increased infection with VSV‐G‐pseudotyped HIV‐1 vectors. The lack of restriction is likely attributable to the fact that dNTP concentrations in SAMHD1‐sufficient mouse cells are higher than the K M of HIV‐1 reverse transcriptase (RT). Consistent with this notion, an HIV‐1 vector mutant bearing an RT with lower affinity for dNTPs was sensitive to SAMHD1‐dependent restriction in cultured cells and in mice. This shows that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism. There is a [Have you seen?][1] (September 2013) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2013.190

Tetherin (Bst-2 CD317) is a cell-surface protein whose expression is induced by IFNα. Although tetherin expression causes the retention of retrovirus particles on the surface of infected cells, it is not known whether tetherin inhibits retroviral replication or pathogenesis in vivo. Mutation of tetherin antagonists often has little effect on retroviral replication in vitro, and, although tetherin can reduce the yield of extracellular viral particles, some studies suggest that tetherin actually enhances direct cell-to-cell viral transmission. We generated tetherin-deficient mice to determine the effect of this protein on murine retrovirus replication and pathogenesis. We find that tetherin markedly inhibits the replication of Moloney murine leukemia virus (Mo-MLV) and is required for the antiretroviral activity of IFNα to be fully manifested in vitro. Surprisingly, Mo-MLV replication and disease progression was not significantly different in WT and tetherin-deficient mice, but this finding was explained by the fact that Mo-MLV infection did not induce detectable tetherin expression on candidate target cells in vivo. Indeed, IFNα induction was required to reveal the anti–Mo-MLV activity of tetherin in vivo. Moreover, LP-BM5, an MLV strain that has been demonstrated to induce immune activation and IFNα expression, achieved higher levels of viremia and induced exaggerated pathology in tetherin-deficient mice. These data indicate that tetherin is a bona fide antiviral protein and can reduce retroviral replication and disease in vivo.

Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during retrovirus infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 d postinfection with Friend retrovirus (FV) compared with mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, Friend retrovirus infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knockout mice at 2 wk postinfection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8⁺ T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against retrovirus infection in vivo.

The HIV-1 envelope (Env) undergoes conformational changes during infection. Broadly neutralizing antibodies (bNAbs) are typically isolated by using soluble Env trimers, which do not capture all Env states. To address these limitations, we devised a vesicular stomatitis virus (VSV)-based probe to display membrane-embedded Env trimers and isolated five bNAbs from two chronically infected donors, M4008 and M1214. Donor B cell receptor (BCR) repertoires identified two bNAb lineages, M4008_N1 and M1214_N1, that class-switched to immunoglobulin G (IgG) and IgA. Variants of these bNAbs reconstituted as IgA demonstrated broadly neutralizing activity, and the IgA fraction of M1214 plasma conferred neutralization. M4008_N1 epitope mapping revealed a glycan-independent V3 epitope conferring tier 2 virus neutralization. A 4.86-Å-resolution cryogenic electron microscopy (cryo-EM) structure of M1214_N1 complexed with CH505 SOSIP revealed another elongated epitope, the V2V5 corridor, extending from V2 to V5. Overall, the VSV_ENV probe identified bNAb lineages with neutralizing IgG and IgA members targeting distinct sites of HIV-1 Env vulnerability.

Gene therapy and its role in the medical field have evolved drastically in recent decades. Studies aim to define DNA-based medicine as well as encourage innovation and the further development of novel approaches. Gene therapy has been established as an alternative approach to treat a variety of diseases. Its range of mechanistic applicability is wide; gene therapy has the capacity to address the symptoms of disease, the body’s ability to fight disease, and in some cases has the ability to cure disease, making it a more attractive intervention than some traditional approaches to treatment (i.e., medicine and surgery). Such versatility also suggests gene therapy has the potential to address a greater number of indications than conventional treatments. Many DNA-based therapies have shown promise in clinical trials, and several have been approved for use in humans. Whereas current treatment regimens for chronic disease often require frequent dosing, DNA-based therapies can produce robust and durable expression of therapeutic genes with fewer treatments. This benefit encourages the application of DNA-based gene therapy to manage chronic diseases, an area where improving efficiency of current treatments is urgent. Here, we provide an overview of two DNA-based gene therapies as well as their delivery methods: adeno associated virus (AAV)-based gene therapy and plasmid DNA (pDNA)-based gene therapy. We will focus on how these therapies have already been utilized to improve treatment of chronic disease, as well as how current literature supports the expansion of these therapies to treat additional chronic indications in the future.