The microbiome is able to modulate immune responses, alter the physiology of the human organism, and increase the risk of viral infections and development of diseases such as cancer. In this review, we address changes in the cervical microbiota as potential biomarkers to identify the risk of cervical intraepithelial neoplasia (CIN) development and invasive cervical cancer in the context of human papillomavirus (HPV) infection. Current approaches for clinical diagnostics and the manipulation of microbiota with the use of probiotics and through microbiota transplantation are also discussed.

In diseases where epigenetic mechanisms are changed, such as cancer, many genes show altered gene expression and inhibited genes become activated. Human endogenous retrovirus type K (HERV-K) expression is usually inhibited in normal cells from healthy adults. In tumor cells, however, HERV-K mRNA expression has been frequently documented to increase. Importantly, HERV-K-derived proteins can act as tumor-specific antigens, a class of neoantigens, and induce immune responses in different types of cancer. In this review, we describe the function of the HERV-K HML-2 subtype in carcinogenesis as biomarkers, and their potential as targets for cancer immunotherapy.

The cervical microbiota composition and diversity of HIV-positive women in the postpartum period is unknown. Using a high-throughput bacterial 16S rRNA gene sequencing, we identified four community state types (CSTs). CST III (Lactobacillusdominant) and CST IV (IV-A, IV-B.1, IV-B.2; high-diversity) were found in 41% and 59% of samples, respectively. We did not find association of any CST to postpartum period (six or twelve months), HPV infection or cytology (normal or lesion). However, five bacterial genera were associated with cervical lesions (Gardnerella, Aerococcus, Schlegelella, Moryella and Bifidobacterium), with significant odds ratio (OR) of 40 (2.28–706) for the presence of Moryella and 3.5 (1.36–8.9) for Schlegelella. Longitudinal analysis of samples at postpartum that regressed (lesion to normal), progressed (normal to lesion) and maintained the cytology (lesion or normal) evidenced Gardnerella with a significantly higher abundance in regressing lesions. In the current study, we report the first data on the cervical microbiota of HIV-positive women in the postpartum period. Consistent with previous studies of HIV-negative cohorts, HIV-positive women present a stable cervical microbiota of high-diversity in the postpartum period. Our results highlight that specific microbiota species may serve as sensors for changes in the cervical microenvironment associated with cervical lesions.

The human cervical microbiome is complex, and its role in health and disease has just begun to be elucidated. In this study, 57 cervical swab samples from 19 HIV/HPV co-infected women were analyzed for both virome and bacteriome composition. Virome analysis focused on circular DNA viruses through rolling circle amplification followed by next-generation sequencing (NGS). Data were assigned to virus families and genera, and HPV types were identified. NGS data of bacterial 16S from a subset of 24 samples were assigned to operational taxonomic units and classified according to vaginal microbiome community state types (CSTs). Four viral families were found: Papillomaviridae, Anelloviridae, Genomoviridae, and Herpesviridae. Papillomavirus reads were more abundant in women with premalignant cervical lesions, which were also strongly associated with multiple (≥3) high-risk HPV infection. Anellovirus read abundance was negatively correlated with host CD4+ T-cell counts. The bacteriome revealed the presence of CST III and CST IV, and women with ≥1% frequency of genomovirus or herpesvirus reads displayed an increased risk of carrying CST IV. By characterizing the composition of the cervical circular DNA viruses and the bacteriome of HIV/HPV co-infected women, we identified putative interactions between these two microorganism communities and their associations with patients’ clinical characteristics, notably immunodeficiency status.

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Retroelements are expressed in diverse types of cancer and are related to tumorigenesis and to cancer progression. We characterized the expression of retroelements in cervical cancer and explored their interplay with HPV infection and their association with expression of neighboring genes. Forty biopsies of invasive cervical carcinoma (squamous cell carcinomas and adenocarcinomas) with genotyped HPV were selected and analyzed for human endogenous retrovirus (HERV) and long interspersed nuclear element 1 (L1) expression through RNA-seq data. We found 8060 retroelements expressed in the samples and a negative correlation of DNA methyltransferase 1 expression with the two most expressed L1 elements. A total of 103 retroelements were found differentially expressed between tumor histological types and between HPV types, including several HERV families (HERV-K, HERV-H, HERV-E, HERV-I and HERV-L). The comparison between HPV mono- and co-infections showed the highest proportion of differentially expressed L1 elements. The location of retroelements affected neighboring gene expression, such as shown for the interleukin-20 gene family. Three HERVs and seven L1 were located close to this gene family and two L1 showed a positive association with IL20RB expression. This study describes the expression of retroelements in cervical cancer and shows their association with HPV status and host gene expression.

A wide spectrum of drugs have been assessed as latency reversal agents (LRA) to reactivate HIV-1 from cellular reservoirs and aid in viral eradication strategies. Histone deacetylase inhibitors (HDACi) have been studied in vitro and in vivo as potential candidates for HIV-1 latency reversion. Suberoylanilide hydroxamic acid (SAHA) and romidepsin (RMD) are two HDACi able to reverse HIV latency, however studies of potential off-target effects on retroelement expression have been limited. Retroelements constitute a large portion of the human genome, and some are considered “fossil viruses” as they constitute remnants of ancient exogenous retroviruses infections. Retroelements are reactivated during certain disease conditions like cancer or during HIV-1 infection. In this study, we analyzed differential expression of retroelements using publicly available RNA-seq datasets (GSE102187 and GSE114883) obtained from uninfected CD4+, and HIV-1 latently infected CD4+ T-cells treated with HDACi (SAHA and RMD). We found a total of 712 and 1,380 differentially expressed retroelements in HIV-1 latently infected cells following a 24-h SAHA and RMD treatment, respectively. Furthermore, we found that 531 retroelement sequences (HERVs and L1) were differentially expressed under both HDACi treatments, while 1,030 HERV/L1 were exclusively regulated by each drug. Despite differences in specific HERV loci expression, the overall pattern at the HERV family level was similar for both treatments. We detected differential expression of full-length HERV families including HERV-K, HERV-W and HERV-H. Furthermore, we analyzed the link between differentially expressed retroelements and nearby immune genes. TRAF2 (TNF receptor) and GBP5 (inflammasome activator) were upregulated in HDACi treated samples and their expression was correlated with nearby HERV (MERV101_9q34.3) and L1 (L1FLnI_1p22.2k, L1FLnI_1p22.2j, L1FLnI_1p22.2i). Our findings suggest that HDACi have an off-target effect on the expression of retroelements and on the expression of immune associated genes in treated CD4+ T-cells. Furthermore, our data highlights the importance of exploring the interaction between HIV-1 and retroelement expression in LRA treated samples to understand their role and impact on “shock and kill” strategies and their potential use as reservoir biomarkers.

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