Recombination is a major mechanism to generate the genetic diversity of HIV-1. Recombination occurs during reverse transcription using information in the two RNAs to generate a hybrid DNA. Therefore, phenotypically distinct recombinants are generated from viruses containing two copies of different RNAs. Only cells that are doubly infected can generate virions containing two different RNAs. To better understand interactions within the HIV-1 population, we examined the dynamics of HIV-1 double infection. We have demonstrated that HIV-1 double infection occurs far more frequently than expected from random events, and preference in virus entry plays a key role in nonrandom double infection. We have measured HIV-1 recombination rates and have demonstrated that HIV-1 recombines at an exceedingly high rate, approximately 10-fold higher than that of murine leukemia virus (MLV) and spleen necrosis virus (SNV). We have also observed that recombination between different HIV-1 subtypes can be far less frequent than within the same subtype. Our analyses indicated that sequence differences in the dimer initiation signal (DIS) of different HIV-1 subtypes drastically decrease the intersubtype recombination rate, most likely from a reduction of heterozygous virus formation. In addition to HIV-1, we have shown that HIV-2 can also undergo frequent recombination. We are currently studying the genetic interactions between HIV-1 and HIV-2, two distinct human lentiviruses. For our future work, we will examine genetic recombination among HIV-1 genomes and determine the viability of the recombinants. We will also expand our work and examine double infection and recombination in human populations. This work will further our understanding of the molecular basis for generating HIV genetic diversity and explore the possible emergence of novel human viruses via recombination. [Corresponds to Hu Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]
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