Live attenuated HIV vaccines: pitfalls and prospects

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Simian immunodeficiency virus (SIV) nef-gene deletion mutants were initially investigated as live attenuated vaccine candidates for AIDS.
• Early observations suggested nef deletion might attenuate pathogenic lentiviruses, offering protection against wild-type simian immunodeficiency virus (SIV) challenge.

Purpose of the Study:

• To review recent studies on live attenuated AIDS virus vaccine candidates, focusing on safety, efficacy, correlates of immune protection, and molecular determinants of virulence/attenuation.

Main Methods:

• Review of recent studies on nef-deletion SIV mutants in macaques.
• Analysis of long-term observations regarding disease progression, immune dysfunction, and vaccine efficacy.
• Evaluation of studies investigating correlates of protective immunity and potential alternative protection mechanisms.

Main Results:

• Nef-deletion SIV mutants retained virulence, slowing but not preventing disease progression in macaques.
• Long-term studies showed immune dysfunction, T-cell depletion, and AIDS development in vaccinated macaques.
• Vaccine efficacy was disappointing, with limited cross-protection and no protection against homologous SIV challenge years post-vaccination.
• Correlates of protective immunity remain undefined, though passive serum transfer and CD8+ T-cell depletion studies suggest alternative mechanisms.
• Virulent progeny with unpredictable genotypes can emerge from initially attenuated viruses due to viral replication and selective pressure.

Conclusions:

• Current live attenuated primate immunodeficiency virus vaccines lack proven long-term safety and efficacy.
• These attenuated viruses remain valuable tools for investigating correlates of protection and molecular determinants of viral immunopathogenesis.