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When a virion encounters a host cell, it will move along the surface until the surface portion of the virus’ envelope registers a cell surface marker that it can bind strongly to (1, Figure 1.3.1). Once attached to what is effectively the virus’ receptor, there is a structural change within the envelope protein that results in viral entry into the host cell. There are typically two mechanisms by which retroviruses enter host cells: pH-dependent and pH-independent (Figure 1.3.2). In the case of pH-dependent entry, the virion is taken into the cell via an endosome. This is often done when cells are trying to degrade pathogens or take in extracellular materials that are trafficked between cells. When the pH is lowered, it triggers a conformational change within the viral envelope protein resulting in viral fusion and capsid entry into the intracellular space (Figure 1.3.2 A). The mechanism behind pH-independent entry is simpler: the virus fuses to the plasma membrane of the host cell after contact with its cognate receptor and the capsid is released into the intracellular space (Figure 1.3.2 B). A common example of pH-dependent entry for retroviruses would be ALV, while a common example of pH-independent entry would be HIV.

At some point between capsid release and entry into the nucleus, the single-stranded viral RNA genome is reverse transcribed into double-stranded cDNA (1, Figure 1.3.3). Within each viral capsid are the viral genome, reverse transcriptase (RT), integrase, nucleotides, and a tRNA primer taken from the previous host cell. This primer binds to the PBS proceeding U5 at the 5′ end of the viral RNA genome. RT transcribes from the PBS to R, where it encounters a strong stop signal. As this strand is being synthesized, RNase H has started to degrade the already-transcribed RNA. Once R has been transcribed, the newly synthesized DNA strand is transferred for the first time to the 3′ end of the viral RNA genome and binds to the other R sequence. DNA synthesis completes to the beginning of the RNA genome again, with RNase H destroying the remainder of the viral RNA genome except for the PPT. As mentioned above, the PPT serves as a primer for second strand synthesis so at this step the second strand begins synthesis from U3 to the PBS at the end of the first strand. Yet again, the polymerase encounters a strong stop signal at the PBS. Now that there is a stretch of cDNA that overlaps with the U3-R-U5 and PBS site, the cDNA loops on itself to complete synthesis of the second strand, resulting in a double-stranded cDNA retroviral genome. Once reverse transcribed, this fragment is bound by integrase and is transported into the nucleus. In the nucleus, integrase identifies an insertion site and makes a short repeat that is cut for retroviral cDNA insertion, generating a new provirus. Upon integration into the host genome, proviruses are – mostly – forever: These sequences are susceptible to mutations that can occur based upon a host’s natural genetic mutation rate, which varies by species. These mutations can range from insertions or deletions that can corrupt ORFs, or removal of an entire provirus through homologous recombination leaving behind a single solo LTR. These mutations are not restricted to the internal sequence of a provirus: mutations can also happen within the 5′ and 3′ LTRs, which results in the two sequences – identical at insertion – to diverge over time.

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Post-insertion into the host genome, the retrovirus then relies upon the host to replicate itself. Once this happens, retroviral RNA is exported to produce both structural proteins, replication enzymes, and to provide progeny RNA for viral packaging. Some of the transcribed viral RNA is produced as a full-length transcript, while the transcript responsible for Env gets spliced (Figure 1.2.3). These contents are trafficked to the surface of a cell where they bud. After budding, they undergo a final step to become an infectious virion where protease cleaves CA and MA to form a proper structure before proceeding to infect new cells.

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