Abstract
BackgroundThe human genome contains multiple LTR elements including human endogenous retroviruses (HERVs) that together account for approximately 8–9% of the genomic DNA. At least 40 different HERV groups have been assigned to three major HERV classes on the basis of their homologies to exogenous retroviruses. Although most HERVs are silenced by a variety of genetic and epigenetic mechanisms, they may be reactivated by environmental stimuli such as exogenous viruses and thus may contribute to pathogenic conditions. The objective of this study was to perform an in-depth analysis of the influence of HIV-1 infection on HERV activity in different cell types.ResultsA retrovirus-specific microarray that covers major HERV groups from all three classes was used to analyze HERV transcription patterns in three persistently HIV-1 infected cell lines of different cellular origins and in their uninfected counterparts. All three persistently infected cell lines showed increased transcription of multiple class I and II HERV groups. Up-regulated transcription of five HERV taxa (HERV-E, HERV-T, HERV-K (HML-10) and two ERV9 subgroups) was confirmed by quantitative reverse transcriptase PCR analysis and could be reversed by knock-down of HIV-1 expression with HIV-1-specific siRNAs. Cells infected de novo by HIV-1 showed stronger transcriptional up-regulation of the HERV-K (HML-2) group than persistently infected cells of the same origin. Analysis of transcripts from individual members of this group revealed up-regulation of predominantly two proviral loci (ERVK-7 and ERVK-15) on chromosomes 1q22 and 7q34 in persistently infected KE37.1 cells, as well as in de novo HIV-1 infected LC5 cells, while only one single HML-2 locus (ERV-K6) on chromosome 7p22.1 was activated in persistently infected LC5 cells.ConclusionsOur results demonstrate that HIV-1 can alter HERV transcription patterns of infected cells and indicate a correlation between activation of HERV elements and the level of HIV-1 production. Moreover, our results suggest that the effects of HIV-1 on HERV activity may be far more extensive and complex than anticipated from initial studies with clinical material.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0156-6) contains supplementary material, which is available to authorized users.
Highlights
The human genome contains multiple LTR elements including human endogenous retroviruses (HERVs) that together account for approximately 8–9% of the genomic DNA
Human immunodeficiency virus 1 (HIV-1)-specific silencing RNAs (siRNA) reverse HERV up-regulation To demonstrate that the observed alterations are associated with HIV-1 infection, we investigated if the up-regulated HERV transcription could be reversed by silencing of HIV-1 transcription using RNA interference assays
In our microarray experiments we observed a significant increase of HERVK (HML-2) transcription only in de novo infected cells but not in the persistently infected cell lines (Figure 2) suggesting that an up-regulation of group HERV-K (HML-2) proviruses occurs preferentially within a short period after infection
Summary
The human genome contains multiple LTR elements including human endogenous retroviruses (HERVs) that together account for approximately 8–9% of the genomic DNA. 8–9% of the human genome is composed of endogenous retroviral elements (HERVs). Full-length HERV sequences possess a genomic organization similar to proviruses of exogenous retroviruses. HERVs were classified in three major classes according to sequence homologies with the polymerase (pol) gene of exogenous animal retroviruses. There is no evidence to date that infectious HERVs are produced in humans, suggesting their genetic material replicates exclusively as part of their host’s genome. This is in sharp contrast to many other mammals, rodents, in which the lines between endogenous and exogenous retroviruses can become very blurred [5]. In some instances only a few mutations or recombination events would be required to reconstitute a replication competent provirus in humans [6,7,8]
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