Anorectal 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. However, it is a big challenge in human studies to unambiguously define the composition of the HIV-1 population present on mucosal surfaces of the recipient, to sample and analyze founder viruses at or near the time of transmission, or to compare the founder viruses in different recipients who have been exposed to an identical virus population to determine if founder viruses in one individual also have an advantage in other individuals. To overcome above limitations and better understand the mechanisms of HIV-1 rectal transmission, we studied the very early virological events using SIV-rhesus macaque model.
We analyzed 524 full-length env sequences from the inoculum, rectal mucosae, axillary lymph node tissues, and plasma of six rhesus macaques at 6 and 10 days post SIV rectal transmission using single genome amplification and Sanger’s sequencing.
We found founder virus sequences were primarily derived from rare variants in the inoculum. Despite exposure with identical viral inoculums, founder virus sequences from different animals are largely different, indicating founder viruses are animal-specific. We also identified the founder virus signature (FVS) that can distinguish dominant founder variants from minor founder variants and untransmitted variants in the inoculum. Importantly, post-transmission defective variants were mainly resulted from frameshift mutations rather than APOBEC derived mutations.
Founder viruses in rectal transmission are animal-specific and primarily deriving from low-abundant variants in the inoculum. Our data support a model of rectal transmission, after viruses gain entry through the anorectal mucosa, the host reduces viral diversity by converting some of the transmitted functional viruses into defective viruses mainly via frameshift mutation. Future study to elucidate the role of FVS and mechanism of frameshift mediated conversion of functional viruses into defective variants may gain new insight into the rectal transmission bottleneck, which may inform the design of new strategies to prevent HIV-1 transmission.