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Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining
Published on: December 23, 2016
TRIM5α does not affect simian immunodeficiency virus SIV(mac251) replication in vaccinated or unvaccinated Indian
Claudio Fenizia1, Brandon F Keele, David Nichols
1Animal Models and Retroviral Vaccines Section, Vaccine Branch, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
TRIM5α is a natural resistance factor that binds retroviral capsid proteins and restricts virus replication. The B30.2/SPRY domain of TRIM5α is polymorphic in rhesus macaques, and some alleles are associated with reduced simian immunodeficiency virus (SIV) SIV(mac251) and SIV(smE543) replication in vivo. We determined the distribution of TRIM5α alleles by PCR and sequence analysis of the B30.2/SPRY domain in a cohort of 82 macaques. Thirty-nine of these macaques were mock vaccinated, 43 were vaccinated with either DNA-SIV/ALVAC-SIV/gp120, ALVAC-SIV/gp120, or gp120 alone, and all were exposed intrarectally to SIV(mac251) at one of three doses. We assessed whether the TRIM5α genotype of the macaques affected the replication of challenge virus by studying the number of SIV variants transmitted, the number of exposures required, the SIV(mac251) viral level in plasma and tissue, and the CD4(+) T-cell counts. Our results demonstrated that TRIM5α alleles, previously identified as restrictive for SIV(mac251) replication in vivo following intravenous exposure, did not affect SIV(mac251) replication following mucosal exposure, regardless of prior vaccination, challenge dose, or the presence of the protective major histocompatibility complex alleles (MamuA01(+), MamuB08(+), or MamuB017(+)). The TRIM5α genotype had no apparent effect on the number of transmitted variants or the number of challenge exposures necessary to infect the animals. DNA sequencing of the SIV(mac251) Gag gene of the two stocks used in our study revealed SIV(mac239)-like sequences that are predicted to be resistant to TRIM5α restriction. Thus, the TRIM5α genotype does not confound results of mucosal infection of rhesus macaques with SIV(mac251).
Insights
The TRIM5α genotype, a natural resistance factor, did not impact simian immunodeficiency virus (SIV) replication in macaques after mucosal exposure. This finding is crucial for understanding SIV infection models and vaccine development.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- TRIM5α acts as a natural barrier against retroviral replication by binding viral capsid proteins.
- Specific TRIM5α alleles in rhesus macaques influence simian immunodeficiency virus (SIV) replication in vivo.
- The B30.2/SPRY domain of TRIM5α exhibits polymorphism, affecting its antiviral activity.
Purpose of the Study:
- To investigate the effect of TRIM5α genotype on SIV(mac251) replication following mucosal exposure in rhesus macaques.
- To determine if TRIM5α genotype influences viral transmission, infectivity, and disease progression in vaccinated and unvaccinated macaques.
- To assess the reliability of SIV(mac251) mucosal challenge models in rhesus macaques concerning TRIM5α restriction.
Main Methods:
- Genotyping of TRIM5α alleles in 82 rhesus macaques using PCR and sequence analysis of the B30.2/SPRY domain.
- Vaccination of macaques with various SIV vaccine candidates or mock vaccination.
- Intrarectal challenge with SIV(mac251) at different doses and assessment of viral load, transmitted variants, exposure requirements, and CD4(+) T-cell counts.
Main Results:
- TRIM5α alleles previously shown to restrict SIV replication after intravenous exposure did not affect replication after mucosal exposure.
- TRIM5α genotype did not influence the number of transmitted SIV variants or the number of exposures needed for infection.
- Sequencing revealed SIV(mac251) Gag gene variants resistant to TRIM5α restriction, suggesting a mechanism for the observed lack of effect.
Conclusions:
- The TRIM5α genotype does not confound the results of SIV(mac251) mucosal infection models in rhesus macaques.
- TRIM5α restriction is less influential in mucosal SIV infection compared to intravenous routes, irrespective of vaccination status or MHC alleles.
- These findings support the use of SIV(mac251) mucosal challenge models for studying antiviral strategies without TRIM5α genotype interference.
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