The replicative activity of human endogenous retrovirus K102 (HERV-K102) with HIV viremia

Human endogenous retrovirus type K (HERV-K) proviruses are scattered throughout the human genome, but as no infectious HERV-K virus has been detected to date, the mechanism by which these viruses replicated and populated the genome remains unresolved. Here, we provide evidence that, in addition to the RNA genomes that canonical retroviruses package, modern HERV-K viruses can contain reverse-transcribed DNA (RT-DNA) genomes. Indeed, reverse transcription of genomic HERV-K RNA into the DNA form is able to occur in three distinct times and locations: (i) in the virus-producing cell prior to viral release, yielding a DNA-containing extracellular virus particle similar to the spumaviruses; (ii) within the extracellular virus particle itself, transitioning from an RNA-containing particle to a DNA-containing particle; and (iii) after entry of the RNA-containing virus into the target cell, similar to canonical retroviruses, such as murine leukemia virus and HIV. Moreover, using a resuscitated HERV-K virus construct, we show that both viruses with RNA genomes and viruses with DNA genomes are capable of infecting target cells. This high level of genomic flexibility historically could have permitted these viruses to replicate in various host cell environments, potentially assisting in their many integration events and resulting in their high prevalence in the human genome. Moreover, the ability of modern HERV-K viruses to proceed through reverse transcription and package RT-DNA genomes suggests a higher level of replication competency than was previously understood, and it may be relevant in HERV-Kassociated human diseases. IMPORTANCERetroviral elements comprise at least 8% of the human genome. Of all the endogenous retroviruses, HERV-K viruses are the most intact and biologically active. While a modern infectious HERV-K has yet to be found, HERV-K activation has been associated with cancers, autoimmune diseases, and HIV-1 infection. Thus, determining how this virus family became such a prevalent member of our genome and what it is capable of in its current form are of the utmost importance. Here, we provide evidence that HERV-K viruses currently found in the human genome are able to proceed through reverse transcription and historically utilized a life cycle with a surprising degree of genomic flexibility in which both RNA-and DNA-containing viruses were capable of mediating infection.

Section: Resultssupporting

confidence: 82%

Genomic Flexibility of Human Endogenous Retrovirus Type K

Dube

Contreras-Galindo

et al. 2014

“…RNA from the viruses of the HERV-H family, of which there are at least 1,000 copies in the human genome as opposed to ϳ50 copies of HERV-K (HML-2), was not detected in plasma (18,19). The finding that plasma HERV-K RNA titers are substantially elevated in HIV-1-infected individuals has now been confirmed by at least two other groups (26,32). As HERV-K (HML-2) bears considerable resemblance to MMTV, which causes mammary tumors in rodents and replicates in lymphocytes (9, 37), we investigated whether titers of HERV-K (HML-2) are also elevated in the plasma of humans with breast cancer or lymphoma.…”

Section: Resultsmentioning

confidence: 88%

“…In the past 2 years, one group has created an infectious clone of HERV-K (HML-2) (23), and another has shown that virus can be generated using several transcomplementary plasmids (32). Thus, at least in its reanimated form with mutations corrected to reintroduce open reading frames, HERV-K (HML-2) can be shown to replicate.…”

mentioning

confidence: 99%

Human Endogenous Retrovirus K (HML-2) Elements in the Plasma of People with Lymphoma and Breast Cancer

Contreras-Galindo

Kaplan

Leissner³

et al. 2008

184

203

Actively replicating endogenous retroviruses entered the human genome millions of years ago and became a stable part of the inherited genetic material. They subsequently acquired multiple mutations, leading to the assumption that these viruses no longer replicate. However, certain human tumor cell lines have been shown to release endogenous retroviral particles. Here we show that RNA from human endogenous retrovirus K (HERV-K) (HML-2), a relatively recent entrant into the human genome, can be found in very high titers in the plasma of patients with lymphomas and breast cancer as measured by either reverse transcriptase PCR or nucleic acid sequence-based amplification. Further, these titers drop dramatically with cancer treatment. We also demonstrate the presence of reverse transcriptase and viral RNA in plasma fractions that contain both immature and correctly processed HERV-K (HML-2) Gag and envelope proteins. Finally, using immunoelectron microscopy, we show the presence of HERV-K (HML-2) virus-like particles in the plasma of lymphoma patients. Taken together, these findings demonstrate that elements of the endogenous retrovirus HERV-K (HML-2) can be found in the blood of modern-day humans with certain cancers.

“…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.…”

mentioning

confidence: 99%

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.