Detection of HERV-K(HML-2) Viral RNA in Plasma of HIV Type 1-Infected Individuals

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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...

Section: Resultsmentioning

confidence: 98%

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confidence: 85%

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

Contreras-Galindo

Kaplan

Dube

et al. 2015

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“…In addition, some HERV have been shown to be associated with some autoimmune diseases and cancers (20,21). In certain circumstances, exogenous retrovirus infections such as HIV-1 have been shown to induce HERV-K expression (6,7,11). We have previously shown that HIV-1-infected adults can mount anti-HERV-specific T cell responses and that an inverse relationship exists between the magnitude of the HERV-specific T cell response and the level of HIV-1 viremia in untreated patients, in both the early (10) and the chronic (23) phases of the disease.…”

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confidence: 97%

Identification of Human Endogenous Retrovirus-Specific T Cell Responses in Vertically HIV-1-Infected Subjects

Tandon

SenGupta

Ndhlovu

et al. 2011

Human endogenous retrovirus (HERV)-specific T cell responses in HIV-1-infected adults have been reported. Whether HERV-specific immunity exists in vertically HIV-1-infected children is unknown. We performed a cross-sectional analysis of HERV-specific T cell responses in 42 vertically HIV-1-infected children. HERV (-H, -K, and -L family)-specific T cell responses were identified in 26 of 42 subjects, with the greatest magnitude observed for the responses to HERV-L. These HERV-specific T cell responses were inversely correlated with the HIV-1 plasma viral load and positively correlated with CD4 + T cell counts. These data indicate that HERV-specific T cells may participate in controlling HIV-1 replication and that certain highly conserved HERV-derived proteins may serve as promising therapeutic vaccine targets in HIV-1-infected children.

“…Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53). Compared to healthy individuals, HIV-1-infected individuals show high levels of HERV-K (HML-2) RNA, DNA, protein, and viral particles in their plasma (45,47,48,50).…”

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confidence: 99%

“…We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53). Compared to healthy individuals, HIV-1-infected individuals show high levels of HERV-K (HML-2) RNA, DNA, protein, and viral particles in their plasma (45,47,48,50). This HIV-1-mediated activation of HERV-K (HML-2) is partially due to the HIV-1 Tat protein activating the NF-B and NF-AT transcription factors, which then interact with the HERV-K (HML-2) LTR promoter to stimulate transcription (46).…”

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confidence: 99%

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

Gonzalez-Hernandez

Cavalcoli

Sartor

et al. 2014

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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.