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

Jian Chen,Qingsheng Li,Guobin Kang,Jianqing Xu,Yanqin Ren,Lance Daharsh,Lu Liu,Yanmin Wan,Qiang Wei

doi:10.3389/fmicb.2018.00557

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.

Highlights

Characterizing the T/F viruses during mucosal infection is important for HIV-1 vaccine and transmission studies (Shaw and Hunter, 2012)
Epidemiological observation suggested that the risk of HIV transmission was higher for anorectal exposure than vaginal exposure(Patel et al, 2014), which might be due to the differences of transmission bottleneck and infection multiplicity (Li et al, 2010; Tully et al, 2016) between modes of sexual transmission
As the transmission of multiple founder variants might associate with faster HIV disease progression (Janes et al, 2015), we hypothesized that characterizing the T/F viruses under a high multiplicity infection setting could provide new insights into the mechanisms of HIV/SIV anorectal transmission

Summary

Introduction

Characterizing the T/F viruses during mucosal infection is important for HIV-1 vaccine and transmission studies (Shaw and Hunter, 2012). By investigating quasispecies complexity in HIV-1 infected individuals, early studies have suggested that genetically diverse viral quasispecies in chronic infections were presumably resulting from one or few closely related T/F viruses (Wolfs et al, 1992; Wolinsky et al, 1992; Zhang et al, 1993; Zhu et al, 1993, 1996; Poss et al, 1995; Long et al, 2000; Learn et al, 2002; Derdeyn et al, 2004; Grobler et al, 2004; Ritola et al, 2004; Sagar et al, 2004, 2009) Based on these observations, Keele and colleagues characterized T/F viruses more precisely using single-genome amplification (SGA) and showed that only a limited number of virus variants are transmitted through mucosal transmission in both human and non-human primate (Keele et al, 2008, 2009) which is widely believed to be the consequence of “transmission bottleneck” selection (Kariuki et al, 2017). More evidence has been provided in non-human primate studies on topically applied ARVs that showed better protection against vaginal transmission (Parikh et al, 2009) than rectal transmission (Cranage et al, 2008)

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