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Cross-Species Transmission and Evolution of SIV Chimpanzee Progenitor Viruses Toward HIV-1 in Humanized Mice.

ABSTRACT: The genetic evolution of HIV-1 from its progenitor virus SIV following cross-species transmission is not well understood. Here we simulated the SIVcpz initial transmission to humans using humanized mice and followed the viral evolution during serial passages lasting more than a year. All three SIVcpz progenitor viruses used, namely LB715 and MB897 (group M) as well as EK505 (group N) readily infected hu-mice resulting in chronic viremia. Viral loads increased progressively to higher set-points and the CD4+ T cell decline became more pronounced by the end of the second serial passage indicating viral adaptation and increased pathogenicity. Viral genomes sequenced at different time points revealed many non-synonymous variants not previously reported that occurred throughout the viral genome, including the gag, pol, env, and nef genes. These results shed light on the potential changes that the SIVcpz genome had undergone during the initial stages of human infection and subsequent spread.

SUBMITTER: Schmitt K

PROVIDER: S-EPMC7432304 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cross-Species Transmission and Evolution of SIV Chimpanzee Progenitor Viruses Toward HIV-1 in Humanized Mice.

Schmitt Kimberly K Curlin James J Remling-Mulder Leila L Moriarty Ryan R Goff Kelly K O'Connor Shelby S Stenglein Mark M Marx Preston P Akkina Ramesh R

Frontiers in microbiology 20200811

The genetic evolution of HIV-1 from its progenitor virus SIV following cross-species transmission is not well understood. Here we simulated the SIVcpz initial transmission to humans using humanized mice and followed the viral evolution during serial passages lasting more than a year. All three SIVcpz progenitor viruses used, namely LB715 and MB897 (group M) as well as EK505 (group N) readily infected hu-mice resulting in chronic viremia. Viral loads increased progressively to higher set-points a ...[more]

PMID: 32849468

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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:Central and eastern chimpanzees are infected with Simian Immunodeficiency Virus (SIV) in the wild, typically without developing acute immunodeficiency. Yet the recent zoonotic transmission of chimpanzee SIV to humans, which were naïve to the virus, gave rise to the Human Immunodeficiency Virus (HIV), which causes AIDS and is responsible for one of the deadliest pandemics in human history. Chimpanzees have likely been infected with SIV for tens of thousands of years and have likely evolved to reduce its pathogenicity, becoming semi-natural hosts that largely tolerate the virus. In support of this view, central and eastern chimpanzees show evidence of positive selection in genes involved in SIV/HIV cell entry and immune response to SIV, respectively. We hypothesise that the population first infected by SIV would have experienced the strongest selective pressure to control the lethal potential of zoonotic SIV, and that population genetics will reveal those first critical adaptations. With that aim we used population genetics to investigate signatures of positive selection in the common ancestor of central-eastern chimpanzees. The genes with signatures of positive selection in the ancestral population are significantly enriched in SIV-related genes, especially those involved in the immune response to SIV and those encoding for host genes that physically interact with SIV/HIV (VIPs). This supports a scenario where SIV first infected the central-eastern ancestor and where this population was under strong pressure to adapt to zoonotic SIV. Interestingly, integrating these genes with candidates of positive selection in the two infected subspecies reveals novel patterns of adaptation to SIV. Specifically, we observe evidence of positive selection in numerous steps of the biological pathway responsible for T-helper cell differentiation, including CD4 and multiple genes that SIV/HIV use to infect and control host cells. This pathway is active only in CD4+ cells which SIV/HIV infects, and it plays a crucial role in shaping the immune response so it can efficiently control the virus. Our results confirm the importance of SIV as a selective factor, identify specific genetic changes that may have allowed our closest living relatives to reduce SIV's pathogenicity, and demonstrate the potential of population genomics to reveal the evolutionary mechanisms used by naïve hosts to reduce the pathogenicity of zoonotic pathogens.

Dataset Information

Cross-Species Transmission and Evolution of SIV Chimpanzee Progenitor Viruses Toward HIV-1 in Humanized Mice.

Publications

Cross-Species Transmission and Evolution of SIV Chimpanzee Progenitor Viruses Toward HIV-1 in Humanized Mice.

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