We propose a novel approach towards the construction of a next generation of safe, genetically stable HIV-1 variants as live-attenuated AIDS vaccines. The current generation of HIV-1 deletion variants is not permanently attenuated, and therefore unsafe. We will use an optimized tissue culture evolution system to gradually force HIV-1 to evolve from an efficiently replicating, complex retrovirus that encodes nine proteins to a simple virus with three-to-five genes that is still able to replicate efficiently. Assuming that natural evolution of retroviruses started with the more simple forms that acquired additional gene functions, we propose to turn around the direction of evolution towards more simple HIV-1 variants. For instance, in pilot evolution experiments, we succeeded in selecting fast-replicating HIV-1 variants that lack three accessory genes. Sequence analysis and reconstruction experiments should reveal the """"""""compensatory strategies"""""""" used by the revertant viruses. These fast-replicating variants will be used for another round of gene deletion and subsequent evolution to regain replication capacity. Thus, repeated cycles of gene deletion and evolutionary adaptation are proposed with the aim to obtain a replicating HIV-1 variant with a minimal number of genes. The potential use of mini-HIV versions as vaccine strain was proposed originally by Howard Temin, although he suggested a completely different route to generate such reagents. Additional safety features will be incorporated into these therapeutic viruses, and we will also attenuate the basic set of viral genes. These combined approaches should generate a safe mini-HIV variant that can be used as a live-attenuated vaccine strain. These viruses will await extensive replication tests to verify their genetic stability, followed by animal tests to screen for their pathogenic potential and their ability to induce a protective immune response.
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