High Expression of Antiviral Proteins in Mucosa from Individuals Exhibiting Resistance to Human Immunodeficiency Virus

Abstract

BackgroundSeveral soluble factors have been reported to have the capacity of inhibiting HIV replication at different steps of the virus life cycle, without eliminating infected cells and through enhancement of specific cellular mechanisms. Yet, it is unclear if these antiviral factors play a role in the protection from HIV infection or in the control of viral replication. Here we evaluated two cohorts: i) one of 58 HIV-exposed seronegative individuals (HESNs) who were compared with 59 healthy controls (HCs), and ii) another of 13 HIV-controllers who were compared with 20 HIV-progressors. Peripheral blood, oral and genital mucosa and gut-associated lymphoid tissue (GALT) samples were obtained to analyze the mRNA expression of ELAFIN, APOBEC3G, SAMHD1, TRIM5α, RNase 7 and SerpinA1 using real-time PCR.ResultsHESNs exhibited higher expression of all antiviral factors in peripheral blood mononuclear cells (PBMCs), oral or genital mucosa when compared with HCs. Furthermore, HIV-controllers exhibited higher levels of SerpinA1 in GALT.ConclusionsThese findings suggest that the activity of these factors is compartmentalized and that these proteins have a predominant role depending on the tissue to avoid the infection, reduce the viral load and modulate the susceptibility to HIV infection.

Progestin‐based contraception regimens modulate expression of putative HIV risk factors in the vaginal epithelium of pig‐tailed Macaques

“…GSEA showed suppression of multiple genes, including Serpin A1 and B1, from the serpin A and B family that have been previously linked to HIV resistance. 20,21,28 GSEA also showed reduced expression by progestin-based HC of many antiviral gene products induced by type I interferons, ISGs, including ISG15, IFIT3, IRF7, MX1, OAS3, and many others. 22 30 In our study, DMPA also enhanced expression of genes like VEGF that have been linked to HIV pathogenesis, 31 and genes from the integrin family including ITGB7, which helps in trafficking and retention of HIV-infected lymphocytes in multiple host sites, thus facilitating viral dissemination.…”

“…9,14 In the current study, we demonstrated that DMPA administration was associated with a signature of gene upregulation and downregu- sex workers. 20,21,28 To supplement traditional testing methods for differential gene expression, we also employed GSEA, which is more sensitive in detecting subtle changes in gene expression, to test for perturbations to any known pathways regulating viral infection.…”

“…The DEGs triggered by both treatments (Table S4) included serpins, cornulin, transglutaminases, cystatins, β-defensin, interleukins 1F6, S100A proteins, and other serine protease inhibitors (downregulated); metalloproteinases and tetraspanin (upregulated). Of note were proteins like serpins ( Figure 5A), including Serpin A1 and Serpin B1 that are known to play key antiviral roles at mucosal surfaces 20,21 and ISGs ( Figure 5B) whose gene expression was reduced further by DMPA use compared to LL. Of note were proteins like serpins ( Figure 5A), including Serpin A1 and Serpin B1 that are known to play key antiviral roles at mucosal surfaces 20,21 and ISGs ( Figure 5B) whose gene expression was reduced further by DMPA use compared to LL.…”

“…To augment our analysis, we queried our microarray data using GSEA and found that several important pathways were affected by HC treatment and menstrual status ( Figure 5). Of note were proteins like serpins ( Figure 5A), including Serpin A1 and Serpin B1 that are known to play key antiviral roles at mucosal surfaces 20,21 and ISGs ( Figure 5B) whose gene expression was reduced further by DMPA use compared to LL. The suppressed ISGs included ISG15, MX1, MX2, IFIT3, IRF7, and OAS3 that have known antiviral properties.…”

“…sex workers 20,21,28. To supplement traditional testing methods for differential gene expression, we also employed GSEA, which is more sensitive in detecting subtle changes in gene expression, to test for perturbations to any known pathways regulating viral infection.GSEA showed suppression of multiple genes, including Serpin A1 and B1, from the serpin A and B family that have been previously linked to HIV resistance 20,21,28. GSEA also showed reduced expression by progestin-based HC of many antiviral gene products induced by type I interferons, ISGs, including ISG15, IFIT3, IRF7, MX1, OAS3, and many others 22,29.…”