Identification of potential HIV restriction factors by combining evolutionary genomic signatures with functional analyses

Abstract

BackgroundKnown antiretroviral restriction factors are encoded by genes that are under positive selection pressure, induced during HIV-1 infection, up-regulated by interferons, and/or interact with viral proteins. To identify potential novel restriction factors, we performed genome-wide scans for human genes sharing molecular and evolutionary signatures of known restriction factors and tested the anti-HIV-1 activity of the most promising candidates.ResultsOur analyses identified 30 human genes that share characteristics of known restriction factors. Functional analyses of 27 of these candidates showed that over-expression of a strikingly high proportion of them significantly inhibited HIV-1 without causing cytotoxic effects. Five factors (APOL1, APOL6, CD164, TNFRSF10A, TNFRSF10D) suppressed infectious HIV-1 production in transfected 293T cells by >90% and six additional candidates (FCGR3A, CD3E, OAS1, GBP5, SPN, IFI16) achieved this when the virus was lacking intact accessory vpr, vpu and nef genes. Unexpectedly, over-expression of two factors (IL1A, SP110) significantly increased infectious HIV-1 production. Mechanistic studies suggest that the newly identified potential restriction factors act at different steps of the viral replication cycle, including proviral transcription and production of viral proteins. Finally, we confirmed that mRNA expression of most of these candidate restriction factors in primary CD4+ T cells is significantly increased by type I interferons.ConclusionsA limited number of human genes share multiple characteristics of genes encoding for known restriction factors. Most of them display anti-retroviral activity in transient transfection assays and are expressed in primary CD4+ T cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0165-5) contains supplementary material, which is available to authorized users.

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

“…Moreover, depolarization of the resting cell membrane potential has been proposed to enhance a Vpu-dependent release of HIV-1 from cells (Hsu et al, 2010), suggesting that Vpu-mediated degradation of ATP1B1 may enhance HIV-1 release through the regulation of plasma membrane depolarization. In addition, CD164 (endolyn) overexpression reduced the infection of a Vpu-deficient virus by 45% (Figure 2B) and was shown to restrict HIV-1 virion production in HEK293T cells upon overexpression (McLaren et al, 2015). Furthermore, both HIV-1 Nef and Vpu were found to downregulate the cell surface expression of CD164 in transfected immortalized T cells (Haller et al, 2014).…”

APOL1 Renal Risk Variants: Fertile Soil for HIV-Associated Nephropathy

“…More recently, Mclaren and colleagues confirmed the anti-retroviral properties of APOL1 (McLaren et al 2015). They started with a bioinformatics approach, seeking genes that are shared among at least some of 9 primate species and that showed evidence for evolutionary selection, i.e.…”

Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State

“…APOBEC3A is preferentially expressed in myeloid cells, and their absence enhances viral DNA accumulation (59), is induced by class I IFN (60), and has been defined as a restriction factor against different retroviruses (61). Finally, 2=-5=-oligoadenylate synthetase 1 (OAS1) has been recently identified as a candidate HIV-1 restriction factor, since its overexpression significantly inhibited viral replication without causing cytotoxic effects (25). Together with other cytokines, OAS1 contributes to trigger a systemic innate immune response against viral replication in acute SIV infection (62).…”

“…More recently, class I interferon (IFN)-induced proteins Mx1 and IFI16 have also been proposed as antiviral restriction factors (23,24). In addition, by combining genetic signatures and functional analyses, as many as 11 new potential restriction factors have been proposed (25). To overcome these constraints, lentiviruses have acquired different mechanisms, such as capsid mutations, escape from sensors of innate immunity (26,27), or incorporation of new genes into the viral genome that can counteract the action of cellular restriction factors.…”