Elucidating the Mechanisms of Reverse Transcription and Recombination

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Frequent recombination contributes significantly to the diversity of the HIV-1 population. We have studied multiple aspects of HIV-1 recombination, including the mechanisms that generate intersubtype recombinants, which are playing an increasingly important role in the current AIDS epidemic. By comparing intra- and intersubtype HIV-1 recombination, we have found that the sequence diversity between different HIV-1 subtypes decreases the crossover events and reduces the replication fitness of the recombinants, thereby causing the loss of newly generated chimeric viruses. Additionally, the dimerization initiation signal (DIS), a 6-nt palindromic sequence in the 5' untranslated region of the viral genome, affects the HIV-1 recombination frequency by two separate mechanisms: first, the identity of the DIS affects the generation of recombinants between genotypes with different DIS by dictating the frequency of viral RNA copackaging; second, discordant DIS sequences in the copackaged RNAs can further decrease crossovers at the 5' end of the viral genome and generate a recombination gradient. As HIV-1 is thought to be a recombinant generated from two distinct primate lentiviruses, we also studied recombination between different AIDS viruses. We demonstrated that recombination can occur between distantly related HIV-1 and HIV-2, as well as group O and group M HIV-1 variants, albeit at low rates. These studies revealed insights into the recombination mechanisms that generate diversity in the HIV-1 genome and potentially novel chimeric viruses. Our efforts in this project are focused on critical steps of reverse transcription including minus-strand DNA transfer and how host restriction factors can affect HIV replication. We are also studying recombination between subtype A viruses and mechanisms that cause a loss of replication fitness in newly generated recombinants. These studies will reveal insights into the replication mechanisms of HIV-1. [Corresponds to Hu Project 1 in the October 2011 site visit report of the HIV Drug Resistance Program]