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Identification of Unequally Represented Founder Viruses Among Tissues in Very Early SIV Rectal Transmission
Jian Chen1, Yanqin Ren1,2, Lance Daharsh3
1Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Scientific Research Center, Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Abstract:
Characterizing the transmitted/founder (T/F) viruses of multi-variant SIV infection may shed new light on the understanding of mucosal transmission. We intrarectally inoculated six Chinese rhesus macaques with a single high dose of SIVmac251 (3.1 × 104 TCID50) and obtained 985 full-length env sequences from multiple tissues at 6 and 10 days post-infection by single genome amplification (SGA). All 6 monkeys were infected with a range of 2 to 8 T/F viruses and the dominant variants from the inoculum were still dominant in different tissues from each monkey. Interestingly, our data showed that a cluster of rare T/F viruses was unequally represented in different tissues. This cluster of rare T/F viruses phylogenetically related to the non-dominant SIV variants in the inoculum and was not detected in any rectum tissues, but could be identified in the descending colon, jejunum, spleen, or plasma. In 2 out of 6 macaques, identical SIVmac251 variants belonging to this cluster were detected simultaneously in descending colon/jejunum and the inoculum. We also demonstrated that the average CG dinucleotide frequency of these rare T/F viruses found in tissues, as well as non-dominant variants in the inoculum, was significantly higher than the dominant T/F viruses in tissues and the inoculum. Collectively, these findings suggest that descending colon/jejunum might be more susceptible than rectum to SIV in the very early phase of infection. And host CG suppression, which was previously shown to inhibit HIV replication in vitro, may also contribute to the bottleneck selection during in vivo transmission.
Insights
Early simian immunodeficiency virus (SIV) infection reveals distinct tissue susceptibility. Rare transmitted/founder viruses in the jejunum/colon, not rectum, suggest early mucosal transmission dynamics.
Area of Science:
- Virology
- Immunology
- Gastroenterology
Background:
- Understanding transmitted/founder (T/F) viruses is crucial for deciphering mucosal transmission of simian immunodeficiency virus (SIV).
- Previous studies highlight the complexity of viral populations established during initial infection.
- The role of specific host factors, like CG dinucleotide frequency, in viral transmission bottlenecks remains an area of active research.
Purpose of the Study:
- To characterize the transmitted/founder (T/F) viral variants established in various tissues following intrarectal inoculation with SIV.
- To investigate the differential distribution and characteristics of T/F viruses across multiple tissues in the early stages of infection.
- To explore the potential influence of host genetic factors, such as CG dinucleotide suppression, on SIV transmission and tissue tropism.
Main Methods:
- Intrarectal inoculation of Chinese rhesus macaques with a high dose of SIVmac251.
- Single genome amplification (SGA) to obtain 985 full-length env sequences from multiple tissues at 6 and 10 days post-infection.
- Phylogenetic analysis and assessment of CG dinucleotide frequency in viral sequences.
Main Results:
- Infection was established with 2 to 8 T/F viruses per macaque, with dominant inoculum variants persisting in tissues.
- A distinct cluster of rare T/F viruses, phylogenetically related to non-dominant inoculum variants, was found in the descending colon, jejunum, spleen, and plasma, but not the rectum.
- These rare T/F viruses and non-dominant inoculum variants exhibited a significantly higher average CG dinucleotide frequency compared to dominant T/F viruses.
Conclusions:
- The descending colon and jejunum may be more susceptible than the rectum to SIV infection in the very early phase.
- Host CG dinucleotide suppression might play a role in the selection bottleneck during in vivo SIV transmission.
- These findings provide insights into the early events of mucosal SIV transmission and tissue tropism.
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