HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses

Contreras-Galindo, Rafael; Kaplan, Mark H.; He, Shirley; Contreras-Galindo, Angie C.; Gonzalez-Hernandez, Marta J.; Kappes, Ferdinand; Dube, Derek; Chan, Stephanie; Robinson, Dan R.; Meng, Fan; Dai, Manhong; Gitlin, Scott D.; Chinnaiyan, Arul M.; Omenn, Gilbert S.; Markovitz, David M.

doi:10.1101/gr.144303.112

Cited by 71 publications

(123 citation statements)

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“…We next asked whether expression of HIV-1 viral proteins increases the production of transmissible HK2 VLPs. The rationale behind this approach is that HIV infection, specifically the expression of the HIV-1 Tat and Vif proteins, has been found in previous studies to enhance expression of HK2 (9,10,24,26,27,85,86). Expression of HIV-1 Tat and Vif, but not Vpu, in NCCIT cells increased the production of transmissible HK2 VLPs containing the Bogota probe, as determined by measuring the number of G418-resistant clones (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These viruses, however, are widely considered to be noninfectious (15,(20)(21)(22)(23). In addition to the findings of HERV-K expression in cancer cell lines, we have found HK2 RNA, proteins, and VLPs in the blood of patients with HIV-1 infection, lymphoma, and breast cancer (9,10,(24)(25)(26)(27); the capacity of these viruses to package HK2 sequences and transmit them to other cells remains to be tested.…”

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confidence: 99%

“…About 85% of these HK2 elements exist as solitary LTRs (solo-LTRs), which originated by recombination between the 5= and 3= LTRs of full-length proviruses, removing the internal gag, pro, pol, and env genes (8). To date, approximately two hundred HK2 elements have been found in the DNA of the modern human as full-length proviruses (3,9,10). A few HK2 loci have been copied by segmental duplication.…”

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confidence: 99%

“…While no single human endogenous retrovirus sequence thus far identified in the genome encodes a complete infectious virus, the diverse HK2 loci in the human genome retain coding capacity for every functional retroviral protein (4,10,(28)(29)(30): the Gag protein, necessary for particle formation and release (31)(32)(33)(34)(35); the Pro protein, necessary for cleavage and maturation of viral proteins (35)(36)(37); the Pol protein, necessary for RNA-dependent DNA replication and integration (38)(39)(40)(41)(42); the accessory protein Rec, which exports unspliced viral RNA from the nucleus to the cytoplasm (43,44); and functional Env proteins (45). Recombination or trans-complementation between these proviruses could lead to the formation of viruses that would be able to package and transmit HK2 sequences (9,(46)(47)(48), as seen with endogenous retroviruses in mice (49)(50)(51).…”

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confidence: 99%

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Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Contreras-Galindo

Kaplan

Dube

et al. 2015

J Virol

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Human endogenous retroviruses (HERV) make up 8% of the human genome. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2, is able to code for all viral proteins and produce virus-like particles, it is not known if these virus particles package and transmit HK2-related sequences. Here, we analyzed the capacity of HK2 for packaging and transmitting HK2 sequences. We created an HK2 probe, termed Bogota, which can be packaged into HK2 viruses, and transfected it into cells that make HK2 particles. Supernatants of the transfected cells, which contained HK2 viral particles, then were added to target cells, and the transmissibility of the HK2 Bogota reporter was tracked by G418 resistance. Our studies revealed that contemporary HK2 virions produced by some teratocarcinoma and breast cancer cell lines, as well as by peripheral blood lymphocytes from lymphoma patients, can package HK2 Bogota probes, and these viruses transmitted these probes to other cells. After transmission, HK2 Bogota transcripts undergo reverse transcription, a step impaired by antiretroviral agents or by introduction of mutations into the probe sequences required for reverse transcription. HK2 viruses were more efficiently transmitted in the presence of HK2 Rec or HIV-1 Tat and Vif. Transmitted Bogota probes formed episomes but did not integrate into the cellular genome. Resistance to integration might explain the relatively low number of HK2 insertions that were acquired during the last 25 million years of evolution. Whether transient transmission of modern HK2 sequences, which encode two putative oncoproteins, can lead to disease remains to be studied. IMPORTANCERetroviruses invaded the genome of human ancestors over the course of millions of years, yet these viruses generally have been inactivated during evolution, with only remnants of these infectious sequences remaining in the human genome. One of these viruses, termed HK2, still is capable of producing virus particles, although these particles have been regarded as being noninfectious. Using a genetic probe derived from HK2, we have discovered that HK2 viruses produced in modern humans can package HK2 sequences and transmit them to various other cells. Furthermore, the genetic sequences packaged in HK2 undergo reverse transcription. The transmitted probe circularized in the cell and failed to integrate into the cellular genome. These findings suggest that modern HK2 viruses can package viral RNA and transmit it to other cells. Contrary to previous views, we provide evidence of an extracellular viral phase of modern HK2 viruses. We have no evidence of sustained, spreading infection.A ctively replicating retroviruses infected the germ line multiple times over the millions of years of human evolution. These sequences were transmitted vertically in a Mendelian fashion to the next generation; therefore, they became a stable part of the inherited genetic material. Relics of these retroviral infections presently make up approximately 8% of the modern human genome. These retro...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Contreras-Galindo

Kaplan

Dube

et al. 2015

J Virol

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“…Tat effects most likely are mediated by cellular transcription factors, such as NF-B and NF-AT, and alterations in chromatin structure (46,85). Interestingly, upon examination of proviruses that are activated by Tat treatment, we observed that some do not contain viable 5=-LTR promoter regions (i.e., the promoters have large regions missing or are truncated or mutated).…”

Section: Discussionmentioning

confidence: 95%

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Gonzalez-Hernandez

Cavalcoli

Sartor

et al. 2014

J Virol

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Approximately 8% of the human genome is made up of endogenous retroviral sequences. As the HIV-1 Tat protein activates the overall expression of the human endogenous retrovirus type K (HERV-K) (HML-2), we used next-generation sequencing to determine which of the 91 currently annotated HERV-K (HML-2) proviruses are regulated by Tat. Transcriptome sequencing of total RNA isolated from Tat-and vehicle-treated peripheral blood lymphocytes from a healthy donor showed that Tat significantly activates expression of 26 unique HERV-K (HML-2) proviruses, silences 12, and does not significantly alter the expression of the remaining proviruses. Quantitative reverse transcription-PCR validation of the sequencing data was performed on Tattreated PBLs of seven donors using provirus-specific primers and corroborated the results with a substantial degree of quantitative similarity. IMPORTANCEThe expression of HERV-K (HML-2) is tightly regulated but becomes markedly increased following infection with HIV-1, in part due to the HIV-1 Tat protein.The findings reported here demonstrate the complexity of the genome-wide regulation of HERV-K (HML-2) expression by Tat. This work also demonstrates that although HERV-K (HML-2) proviruses in the human genome are highly similar in terms of DNA sequence, modulation of the expression of specific proviruses in a given biological situation can be ascertained using next-generation sequencing and bioinformatics analysis.

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The Evolution of CentromericDNASequences

Brown

O’Neill

2014

Encyclopedia of Life Sciences

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For most eukaryotic species, the centromere is comprised of millions of base pairs of tandemly repeated deoxyribonucleic acid (DNA) sequences. Centromere function is broadly conserved across eukaryotic phyla, yet centromere DNA presents several unique conundrums for biologists, further complicated by the challenges in studying highly repeated regions of complex genomes. Contrary to the expectation that centromeric sequences would be constrained to maintain centromere function across species, these sequences are among the most rapidly evolving sequences in any given genome. This discordance between functional constraint and sequence divergence, termed the ‘centromere paradox’, appears to defy basic laws of Mendelian inheritance. Multiple genetic mechanisms have been proposed to explain centromeric DNA complexity and rapid evolutionary divergence, taking into consideration the unique chromosome architecture and dynamics of the centromere during both mitosis and meiosis. Stochastic processes affecting sequence evolution and the selective constraint necessary for centromere protein recognition are balanced in an ongoing conflict that ultimately manifests as rapid centromere DNA evolution. Key Concepts: Loss of centromere function does not equate to loss of centromere sequence. Conversely, centromere sequences do not strictly demarcate a functional centromere. The constitution of centromeric satellite DNAs across species differs not only in sequence, but also in the repeat unit length, abundance of the repeat unit and the complexity of the genomic structure of multiple repeat units. The more commonly found regional centromere is typified by a distinct, linear organisation of a given satellite repeat unit into high‐copy tandem repeats of that unit than can span megabases of DNA. The high homology of the higher‐order satellite repeats within a centromere is consistent with their function to effectively bind centromere proteins, wherein selection may favour homogeneity to retain centromere function. Initial forms of an active centromere do not necessarily require HOR satellite arrays, but rather such arrays evolve over evolutionary timescales following stable establishment and inheritance of a new centromere. The process of molecular drive, involving concerted evolution and gene conversion results in the homogenisation and fixation of a given repeat variant and may lead to the convergent and concerted evolution of satellites within one species. Genetic conflict and/or meiotic drive may be responsible for the different centromere satellite sequence suites found between species. Centromere Drive may be responsible for the rapid divergence of functional centromeric sequences between species. The coding sequences for two centromere proteins, CENP‐A (centromere‐specific histone H3) and CENP‐C (a centromere‐specific DNA binding protein), evolve at rates faster than expected for either neutral (unconstrained) or purifying (selectively constrained) evolution in many species. Mobile elements can impact the rate at which satellites are derived, expand, contract and homogenise within a species.

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HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses

Cited by 71 publications

References 51 publications

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

The Evolution of CentromericDNASequences

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