Evolution of Live-Attenuated HIV Vaccines - Safety concerns remain for developing replicating vectors based on the pathogen human immunodeficiency virus type 1. - BioPharm International

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Evolution of Live-Attenuated HIV Vaccines
Safety concerns remain for developing replicating vectors based on the pathogen human immunodeficiency virus type 1.


BioPharm International Supplements
Volume 24, pp. s4-s8

Dox-Controlled Virus for Delivering RNAi Therapeutics

We also explored the potential of the HIV-rtTA variant as a replicating vector for the efficient delivery of inhibitory gene cassettes that are based on the RNA interference (RNAi) mechanism. More specifically, we introduced an RNA polymerase III-driven short hairpin RNA (shRNA) cassette against wild-type HIV-1 sequences in the context of the dox-dependent virus.42 The shRNA targets the viral nef sequence, which is present in wild-type HIV-1 but not in the HIV-rtTA vector where the nef gene has been replaced by the rtTA gene. A spreading infection of this therapeutic HIV-rtTA-shRNAnef variant in HIV-susceptible cells can be controlled by transient dox treatment. Subsequent dox withdrawal generates cells that contain a silent integrated provirus with a constitutively active shRNAnef expression cassette. As a result, cells are harnessed with shRNAs that efficiently inhibit replication of wild-type HIV-1. This strategy seems particularly suitable for patients infected with a multidrug-resistant virus that can no longer be treated with the current antivirals. This HIV-rtTA-shRNAnef variant may allow interesting combinations of vaccination and RNAi-inhibition strategies. When used as a prophylactic vaccine, the RNAi cargo of this virus will protect all infected cells against a future exposure to HIV-1, thus boosting vaccine protection. When used as a therapeutic virus, the vaccine effect may boost the RNAi-mediated virus inhibition.

Conclusion

Obvious safety concerns remain for developing replicating vectors based on the human pathogen HIV-1. One of the major concerns is that attenuated HIV-1 variants also cause a chronic infection. This fact, combined with the high mutation and recombination rate of HIV-1, may result in the generation of variants with altered replication characteristics over time. However, the dox-controlled HIV-rtTA variant will cause a latent infection on dox-withdrawal, with silent integrated proviruses that will less likely contribute to ongoing virus evolution because they are transcriptionally inactive. Another concern is that the vector may integrate near the 5' end of a proto-oncogene. In this position, the viral LTR-promoter may activate proto-oncogene expression, which could result in cell proliferation, and ultimately cause cancer. Such insertional oncogenesis occurred in 5 out of 20 patients who were treated with a gamma-retroviral vector,43,44 but the new generation lentiviral vectors were designed to be more safe, which is upheld in recent trials.45,46 The tetO-LTR promoter in our HIV-rtTA vectors is inactive on dox-withdrawal, which will strongly reduce the risk of activation of adjacent genes.

We recently constructed a similar dox-dependent SIV variant, which is currently being used to study the efficacy and safety of a conditionally live virus vaccine against AIDS in macaques.47 This SIV variant may be a particularly attractive tool to study the correlates of immune protection on vaccination because the level and duration of replication can be controlled by dox administration. As a next step, the genetic stability and immunogenicity of the HIV-rtTA variant could be tested in mice with a humanized immune system.48,49 These results should indicate whether we can proceed on the risky path toward a live-attenuated HIV-1 vaccine.

Acknowledgements

This research was funded by the Dutch AIDS Foundation (Aids Fonds Netherlands grants 7007, 2005–022, 2007–025), the Technology Foundation STW (applied science division of NWO and the technology program of the Ministry of Economic Affairs, The Netherlands), Zon-Medical Sciences (MW; VICI grant), and NWO-Chemical Sciences (CW; TOP grant).

BEN BERKHOUT, PhD, is head of the Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands, 31.20 5663396,


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