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Abstract
Human immunodeficiency virus type 1 (HIV-1) and other retroviruses replicate through
reverse transcription, a process in which the single stranded RNA of the viral genome
is converted to a double stranded DNA. The virally encoded reverse transcriptase (RT)
mediates reverse transcription through DNA polymerase and RNase H activities. Conversion
of the plus strand RNA to plus/minus strand RNA/DNA hybrid involves a transfer of
the growing DNA strand from one site on the genomic RNA to another. This is called
minus strong-stop DNA transfer. Later synthesis of the second or plus DNA strand involves
a second strand transfer, involving a similar mechanism as the minus strand transfer.
A basic feature of the strand transfer mechanism is the use of the RT RNase H to remove
segments of the RNA template strand from the growing DNA strand, freeing a single
stranded region to anneal to the second site. Viral nucleocapsid protein (NC) functions
to promote transfer by facilitating this strand exchange process. Two copies of the
RNA genomes, sometimes non-identical, are co-packaged in the genomes of retroviruses.
The properties of the reverse transcriptase allow a transfer of the growing DNA strand
between these genomes to occur occasionally at any point during reverse transcription,
producing recombinant viral progeny. Recombination promotes structural diversity of
the virus that helps it to survive host immunity and drug therapy. Recombination strand
transfer can be forced by a break in the template, or can occur at sites where folding
structure of the template pauses the RT, allowing a concentration of RNase H cleavages
that promote transfers. Transfer can be a simple one-step process, or can proceed
by a complex multi-step invasion mechanism. In this latter process, the second RNA
template interacts with the growing DNA strand well behind the DNA 3'-terminus. The
newly formed RNA-DNA hybrid expands by branch migration and eventually catches the
elongating DNA primer 3'-terminus to complete the transfer. Transfers are also promoted
by interactions between the two RNA templates, which accelerate transfer by a proximity
effect. Other details of the role of strand transfers in reverse transcription and
the biochemical features of the transfer reaction are discussed.