Human endogenous retroviruses (HERVs) comprise over 8% of the human genome, accounting for more than twice the percentage of the genome encoding all known genes. Further, these viral residents of the human genome have been found to have biological ramifications (one HERV gene product is vital for human placental development) and their activation is associated with numerous human diseases. Despite their magnitude and potential importance, very little is actually known about the manner in which these viruses carried out their infection and replication cycles. Human endogenous retrovirus type K (HERV-K) is the most recent of the HERVs to have entered the human genome, with the youngest having integrated in the last 200,000 years. Due to their recent integration, while most HERV genomes have been mutated and deleted to render their open reading frames non-functional, many of the more than 91 HERV-K genomes present maintain intact open reading frames for their viral proteins (gag, pol, prt, env). Further, HERV-K mRNAs, proteins, and even viral- like particles have been found to be activated in patients with HIV-1 infection and numerous malignancies, including lymphoma, melanoma, and others. While an infectious HERV-K particle has yet to be identified, two groups have recently resuscitated infectious HERV-K progenitor viruses based on the consensus sequence of the most complete family members. Combining the use of such a progenitor virus with tissue culture and patient sample-based assays, will allow us for the first time to investigate questions pertaining to how HERV-K replicated historically and became such a major portion of the human genetic makeup. Indeed, recent data acquired in our laboratory brings into contention the commonly held belief that HERV-K replicated using the canonical retroviral pathway. Rather, we have found HERV-K particles from both tissue culture cell lines and patient plasma that contain viral DNA genomes, rather than the canonical RNA genomes, suggesting a life cycle more similar to the Spumavirus genus. As such, we hypothesize that historically HERV-K replication occurred using late stage reverse transcription in the infected cell, thereafter packaging viral DNA genomes inside budding particles, and that it was these particles that were important for downstream infection. We will test this hypothesis in three specific aims designed to characterize the nucleic acid constituents of HERV-K viral genomes, clarify the mechanism by which HERV-K packages its viral genome, and ascertain the importance of viral DNA genomes on the historical infection process of HERV-K. The proposed experiments will help elucidate the biology of these viruses in both a historical and contemporary context, begin to clarify the means by which they populated the human genome to the current extent, and potentially identify superior means by which to study HERV-K activation status as a biomarker or causative agent of human disease.
Human Endogenous Retrovirus K (HERV-K) has been associated with several severe human diseases including, but not limited to, auto-immune diseases, HIV-1 infection, and multiple malignancies. The goal of this project is to better understand the viral lifecycle of the HERV-K family, both in its historical and contemporary context.
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|Contreras-Galindo, Rafael; Kaplan, Mark H; Dube, Derek et al. (2015) Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K-Related Sequences. J Virol 89:7187-201|
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