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Macaques infected with attenuated simian immunodeficiency virus resist superinfection with virulence-revertant virus
S A Sharpe1, A M Whatmore, G A Hall
1Centre for Applied Microbiology and Research, Porton Down, Salisbury, UK.
Abstract:
Macaques infected with attenuated simian immunodeficiency virus (SIVmac) can resist superinfection challenge with virulent virus, showing the potential of live attenuated virus as an AIDS vaccine. Superinfection resistance does not, however, prevent the generation of virulent virus in vivo, suggesting that such virus may circumvent the resistance effect. Here, we show that three macaques already infected with the attenuated molecular clone SIVmacC8 were resistant to superinfection with virulent virus that arose in vivo following repair of a 12 bp attenuating lesion in the nef/3' LTR. In contrast, four naive animals became infected following inoculation with blood taken from the macaque in which virulent virus arose. Loss of nef-specific cytotoxic T lymphocyte (CTL) responses followed repair of the attenuating lesion within nef in the donor animal, suggesting the possibility of escape from CTL-driven selection pressure.
Insights
Live attenuated simian immunodeficiency virus (SIVmac) in macaques confers resistance to superinfection. However, virulent SIVmac can still emerge in vivo, potentially evading immune responses like cytotoxic T lymphocytes (CTLs).
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Live attenuated simian immunodeficiency virus (SIVmac) infection in macaques can prevent superinfection with virulent strains.
- This resistance highlights the potential of live attenuated virus vaccines for acquired immunodeficiency syndrome (AIDS).
- However, virulent SIVmac can still emerge in vivo, suggesting mechanisms to overcome vaccine-induced protection.
Purpose of the Study:
- To investigate if macaques infected with an attenuated SIVmac clone resist superinfection by virulent virus arising in vivo.
- To determine if virulent SIVmac emerging in vivo can infect naive animals.
- To explore the role of cytotoxic T lymphocyte (CTL) responses in the escape of virulent SIVmac.
Main Methods:
- Infection of macaques with an attenuated SIVmac molecular clone (SIVmacC8).
- Monitoring for superinfection with virulent SIVmac that arose in vivo after repair of an attenuating lesion.
- Inoculation of naive macaques with blood from animals where virulent virus emerged.
- Assessment of nef-specific CTL responses.
Main Results:
- Macaques infected with attenuated SIVmacC8 resisted superinfection with virulent SIVmac that emerged in vivo.
- Naive macaques became infected when inoculated with blood from the donor macaque harboring emergent virulent virus.
- Loss of nef-specific CTL responses was observed following the repair of the attenuating lesion in the donor animal.
Conclusions:
- Attenuated SIVmac infection can confer resistance to superinfection, but virulent virus can still emerge in vivo.
- Emergent virulent SIVmac can infect naive hosts, indicating a potential failure of vaccine-induced protection.
- Escape from CTL-driven selection pressure may be a mechanism by which virulent SIVmac circumvents host resistance.