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Identification of Unequally Represented Founder Viruses Among Tissues in Very Early SIV Rectal Transmission.

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.

SUBMITTER: Chen J

PROVIDER: S-EPMC5884942 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of Unequally Represented Founder Viruses Among Tissues in Very Early SIV Rectal Transmission.

Chen Jian J Ren Yanqin Y Daharsh Lance L Liu Lu L Kang Guobin G Li Qingsheng Q Wei Qiang Q Wan Yanmin Y Xu Jianqing J

Frontiers in microbiology 20180329

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 domi ...[more]

PMID: 29651274

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Project description:A better understanding of HIV-1 transmission is critical for developing preventative strategies. To that end, we analyzed 524 full-length env sequences of SIVmac251 at 6 and 10 days post intrarectal infection of rhesus macaques. There was no tissue compartmentalization of founder viruses across plasma, rectal and distal lymphatic tissues for most animals; however one animal has evidence of virus tissue compartmentalization. Despite identical viral inoculums, founder viruses were animal-specific, primarily derived from rare variants in the inoculum, and have a founder virus signature that can distinguish dominant founder variants from minor founder or untransmitted variants in the inoculum. Importantly, the sequences of post-transmission defective viruses were phylogenetically associated with competent viral variants in the inoculum and were mainly converted from competent viral variants by frameshift rather than APOBEC mediated mutations, suggesting the converting the transmitted viruses into defective viruses through frameshift mutation is an important component of rectal transmission bottleneck.SignificanceAnorectal receptive intercourse is a common route of HIV-1 transmission and a better understanding of the transmission mechanisms is critical for developing HIV-1 preventative strategies. Here, we report that there is no tissue compartmentalization of founder viruses during very early rectal transmission of SIV in the majority of rhesus macaques and founder viruses are preferentially derived from rare variant in the inoculum. We also found that founder viruses are animal-specific despite identical viral inoculums. After viruses cross the mucosal barriers, the host further reduces viral diversity by converting some of the transmitted functional viruses into defective viruses through frameshift rather than APOBEC derived mutations. To our knowledge, this is the first study of founder viruses at multiple tissue sites during very early rectal transmission.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whole-genome analysis has identified five large clades worldwide which emerged in 2019 (19A and 19B) and in 2020 (20A, 20B, and 20C). This study aimed to analyze the diffusion of SARS-CoV-2 in Spain using maximum-likelihood phylogenetic and Bayesian phylodynamic analyses. The most recent common ancestor (MRCA) of the SARS-CoV-2 pandemic was estimated to have emerged in Wuhan, China, around 24 November 2019. Phylogenetic analyses of the first 12,511 SARS-CoV-2 whole-genome sequences obtained worldwide, including 290 from 11 different regions of Spain, revealed 62 independent introductions of the virus in the country. Most sequences from Spain were distributed in clades characterized by a D614G substitution in the S gene (20A, 20B, and 20C) and an L84S substitution in ORF8 (19B) with 163 and 118 sequences, respectively, with the remaining sequences branching in 19A. A total of 110 (38%) sequences from Spain grouped in four different monophyletic clusters of clade 20A (20A-Sp1 and 20A-Sp2) and 19B clade (19B-Sp1 and 19B-Sp2) along with sequences from 29 countries worldwide. The MRCAs of clusters 19A-Sp1, 20A-Sp1, 19A-Sp2, and 20A-Sp2 were estimated to have occurred in Spain around 21 and 29 January and 6 and 17 February 2020, respectively. The prevalence of clade 19B in Spain (40%) was by far higher than in any other European country during the first weeks of the epidemic, probably as a result of a founder effect. However, this variant was replaced by G614-bearing viruses in April. In vitro assays showed an enhanced infectivity of pseudotyped virions displaying the G614 substitution compared with those having D614, suggesting a fitness advantage of D614G.IMPORTANCE Multiple SARS-CoV-2 introductions have been detected in Spain, and at least four resulted in the emergence of locally transmitted clusters that originated not later than mid-February, with further dissemination to many other countries around the world, and a few weeks before the explosion of COVID-19 cases detected in Spain during the first week of March. The majority of the earliest variants detected in Spain branched in the clade 19B (D614 viruses), which was the most prevalent clade during the first weeks of March, pointing to a founder effect. However, from mid-March to June 2020, G614-bearing viruses (clades 20A, 20B, and 20C) overcame D614 variants in Spain, probably as a consequence of an evolutionary advantage of this substitution in the spike protein. A higher infectivity of G614-bearing viruses than D614 variants was detected, suggesting that this substitution in SARS-CoV-2 spike protein could be behind the variant shift observed in Spain.

Dataset Information

Identification of Unequally Represented Founder Viruses Among Tissues in Very Early SIV Rectal Transmission.

Publications

Identification of Unequally Represented Founder Viruses Among Tissues in Very Early SIV Rectal Transmission.

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