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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI047017-02
Application #
6374429
Study Section
Special Emphasis Panel (ZRG1-VACC (03))
Program Officer
Sharma, Opendra K
Project Start
2000-04-15
Project End
2002-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$150,000
Indirect Cost
Name
Universiteit Van Amsterdam
Department
Type
DUNS #
489649857
City
Amsterdam
State
Country
Netherlands
Zip Code
Das, Atze T; Jeeninga, Rienk E; Berkhout, Ben (2010) Possible applications for replicating HIV 1 vectors. HIV Ther 4:361-369
Jeeninga, Rienk E; Jan, Barbara; van der Linden, Birgit et al. (2005) Construction of a minimal HIV-1 variant that selectively replicates in leukemic derived T-cell lines: towards a new virotherapy approach. Cancer Res 65:3347-55
Hunter, C A; Suzuki, Y; Subauste, C S et al. (1996) Cells and cytokines in resistance to Toxoplasma gondii. Curr Top Microbiol Immunol 219:113-25