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INTRODUCTION Around 1.7 million children are estimated to live with HIV-1 worldwide, and about 160,000 infants are newly infected every year. Since adaptive immunity takes time to mature and develop in infants, and maternal antibodies provide limited antiviral activity, innate and intrinsic immunity against HIV-1 in the young is of critical importance. Intrinsic restriction factors are cellular proteins that effectively inhibit HIV-1 replication in vitro, but there is limited understanding of their role in vivo, and little to no data has been reported on the expression of host restriction factors in children. We hypothesized that restriction factor expression might be particularly important in children living with HIV-1 and correlate with disease progression. METHODS We analyzed gene expression of APOBEC3A, APOBEC3C, APOBEC3G, APOBEC3H, SAMHD1, ISG15, CDKN1A, MX2, TRIM5, and SLFN11 by qPCR in 121 samples of CD4+ T cells from vertically infected children living with HIV-1. Cell surface expression of BST-2/tetherin and markers of CD4+ T-cell activation were analyzed by flow cytometry. RESULTS After adjusting for gender and age, BST-2/tetherin expression on CD4+ T cells showed significant positive correlation with viral load (P = 0.0006; ρ = 0.33), CD4+ T-cell activation (P < 0.0001; ρ = 0.53), CD8+ T-cell activation (P < 0.0001; ρ = 0.53), and a negative correlation with CD4+ T-cell counts (P = 0.0008; ρ = -0.33). The expression of SAMHD1 correlated negatively with markers of T-cell activation (P = 0.046; ρ = -0.22). DISCUSSION These results suggest an important role of some restriction factors in the pathogenesis of HIV-1 in children.

In people living with HIV (PLWH), chronic inflammation can lead to cancer initiation and progression, besides driving a dysregulated and diminished immune responsiveness. HIV infection also leads to increased transcription of Human Endogenous Retroviruses (HERVs), which could increase an inflammatory environment and create a tumor growth suppressive environment with high expression of pro-inflammatory cytokines. In order to determine the impact of HIV infection to HERV expression on the breast cancer microenvironment, we sequenced total RNA from formalin-fixed paraffin-embedded (FFPE) breast cancer samples of women HIV-negative and HIV-positive for transcriptome and retrotranscriptome analyses. We performed RNA extraction from FFPE samples, library preparation and total RNA sequencing (RNA-seq). The RNA-seq analysis shows 185 differentially expressed genes: 181 host genes (178 upregulated and three downregulated) and four upregulated HERV transcripts in HIV-positive samples. We also explored the impact of HERV expression in its neighboring breast cancer development genes (BRCA1, CCND1, NBS1/NBN, RAD50, KRAS, PI3K/PIK3CA) and in long non-coding RNA expression (AC060780.1, also known as RP11-242D8.1). We found a significant positive association of HERV expression with RAD50 and with AC060780.1, which suggest a possible role of HERV in regulating breast cancer genes from PLWH with breast cancer. In addition, we found immune system, extracellular matrix organization and metabolic signaling genes upregulated in HIV-positive breast cancer. In conclusion, our findings provide evidence of transcriptional and retrotranscriptional changes in breast cancer from PLWH compared to non-HIV breast cancer, including dysregulation of HERVs, suggesting an indirect effect of the virus on the breast cancer microenvironment.

Schizophrenia genome-wide association studies highlight the substantial contribution of risk attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. These ancient viral elements have previously been overlooked in genetic and transcriptomic studies due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, we found that the fraction of the genome where HERVs are located (the ‘retrogenome’) is enriched for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors for schizophrenia and potential diagnostic biomarkers and treatment targets.

Much has been learnt from the functions of host restriction factors during acute and chronic HIV-1 infection, but far less is known about their role in HIV-1-infected individuals in which viral load is stably suppressed with antiretroviral therapy (ART). In this study transcriptional expression of 42 host restriction factors was determined for memory CD4+ T cells sorted from 10 uninfected and 21 HIV-1-infected individuals, treated with suppressive ART and for which the viral reservoir was quantified. No significant associations were observed between restriction factor expression and HIV-1 reservoir size, quantified by measurement of HIV-1 Gag DNA using droplet digital polymerase chain reaction, and by measurement of replication-competent inducible virus using quantitative viral outgrowth assays. Expression of eight of the restriction factors differed significantly, and with a false discovery rate of

HIV-1 persistence in latent reservoirs during antiretroviral therapy (ART) is the main obstacle to virus eradication. To date, there is no marker that adequately identifies latently infected CD4+ T cells in vivo. Using a well-established ex vivo model, we generated latently infected CD4+ T cells and identified interferon-induced transmembrane protein 1 (IFITM1), a transmembrane antiviral factor, as being overexpressed in latently infected cells. By targeting IFITM1, we showed the efficient and specific killing of a latently infected cell line and CD4+ T cells from ART-suppressed patients through antibody-dependent cytolysis. We hypothesize that IFITM1 could mark natural reservoirs, identifying an immune target for killing of latently infected cells. These novel insights could be explored to develop clinical therapeutic approaches to effectively eradicate HIV-1.