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Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys
1Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA. newstein@massmed.org
Abstract:
Mutations in human immunodeficiency virus type 1 reverse-transcriptase codons 89 and 184 confer inhibitor resistance and alter the mutation spectrum of the enzyme. Six macaques were inoculated with wild-type or mutated derivatives (E89G or E89G and M184V) of simian immunodeficiency virus macaque (SIVmac) 239. Five of the infected monkeys maintained high virus loads; the sixth, which was infected with the E89G mutant strain, maintained viremia at a level below the limit of detection. Sequence analysis demonstrated substantial reversion of the E89G mutation in the animals with progressive infection and preservation of this mutation in the animal with controlled infection. A P272S mutation occurred at high frequency in the viruses containing M184V, which did not revert. These results demonstrate that the E89G mutation has a significant negative impact on SIVmac fitness, whereas SIVmac bearing M184V achieved high, sustained virus loads, perhaps with a compensatory effect of the P272S mutation.
Insights
Investigating simian immunodeficiency virus (SIVmac) mutations E89G and M184V in macaques revealed E89G reduces viral fitness, while M184V maintains high viral loads, potentially aided by P272S.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Mutations in human immunodeficiency virus type 1 (HIV-1) reverse-transcriptase codons 89 and 184 are known to confer inhibitor resistance and alter enzyme mutation patterns.
- Simian immunodeficiency virus macaque (SIVmac) serves as a crucial model for studying HIV-1 pathogenesis and therapeutic strategies.
Purpose of the Study:
- To investigate the in vivo fitness and evolutionary dynamics of SIVmac strains with specific reverse-transcriptase mutations (E89G and M184V).
- To assess the impact of these mutations on viral load, mutation stability, and potential compensatory mechanisms in a macaque model.
Main Methods:
- Six macaques were inoculated with wild-type SIVmac 239 or its derivatives containing E89G or E89G and M184V mutations.
- Viral loads were monitored, and sequence analysis was performed to track mutation dynamics and identify secondary mutations.
Main Results:
- Infection with the E89G mutant strain resulted in controlled viremia below the limit of detection in one macaque.
- Progressive infections showed substantial reversion of the E89G mutation, while it was preserved in the controlled infection.
- The M184V mutation was associated with high, sustained viral loads and the frequent occurrence of a non-reverting P272S mutation.
Conclusions:
- The E89G mutation significantly impairs SIVmac fitness in vivo.
- The M184V mutation allows SIVmac to achieve high viral loads, possibly due to compensatory effects of the P272S mutation.
- These findings highlight the complex interplay between specific mutations, viral fitness, and disease progression in SIV infection.