Student Theses and Dissertations

Young Nam Lee

Date of Award

2010

Document Type

Thesis

RU Laboratory

Bieniasz Laboratory

Keywords

retroviruses, human endogenous retroviruses (HERV), HERV-K, HIV-1, HERV-K (HML-2) life cycle

Abstract

Retroviruses are a family of clinically significant and scientifically fascinating viruses that infect a wide array of organisms from all vertebrate classes. The two hallmark events in the life cycle of retroviruses are the reverse transcription of the single stranded RNA (ssRNA) genome generating a double stranded DNA (dsDNA) and the integration of this dsDNA into the host genome. Because integration is irreversible and the infected cells are usually difficult to target for elimination in the host, the infection is generally permanent. HIV-1, the most important and well-studied member of all retroviruses, is the causative agent of acquired immune deficiency syndrome (AIDS) for which no vaccine or cure is known. Since recognition of the AIDS epidemic, around 25 million people have died from HIV-1 related causes, including 2 million in 2007. Currently, 33 million people are believed to be living with the virus, with most of these people living in sub-Saharan Africa, where 67% of all infected people reside and 75% of AIDS deaths occurred in 2007. When retroviruses infect germ cells or germ cell progenitors, the virus can become endogenized. These viruses, called endogenous retroviruses (ERV), make up more than 8% of the human genome. The integrated virus will be present in the genome of all cells of the individual derived from the infected germ cell, and be passed on to progeny in a Mendelian manner to following generations. Both chance and the insertion’s effect on the fitness of the host can determine the allelic frequency in the population. Hence, elements which produce large quantities of viral proteins and progeny or elements that insert into a necessary gene will likely reduce the fitness of the host and as an allele will be negatively selected in the host population. Currently, there is no known replication competent HERV, as most proviruses are filled with deletions and premature stop codons. However, one family of Class II HERV, HERV-K(HML-2), seems to have been replicating until recently. The HERV-K(HML-2) family includes human specific members and elements that are polymorphic in the human population, suggesting replication since the divergence of humans from chimpanzees 6 million years ago and potentially more recently as well. In this body of work, the problem of the lack of a replication competent virus sequence is circumvented by deducing a consensus sequence from the youngest set of HERV proviruses. Named HERV-KCON, we find that many of its components are functional individually and together enable infection of target cells in a single-cycle infection system. Using this system, we have characterized the previously unknown aspects of HERV-K(HML-2) life cycle, such as location of assembly and budding, dependency on cell replication, and more extensively, its ntegration site preference. HERV-KCON’s interaction with current anti-retroviral host proteins is accessed, and evidence of the same interaction occurring in vivo is presented in the context of APOBEC3G.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/360

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