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. Keywords: HIV-1 evolution from SIVcpz, cross-species viral transmission, SIVcpz evolution into HIV-1, modeling SIV evolution into HIV using humanized mice, SIV pathogenesis in humanized mice, origin of human pathogens in NHP, SIV genetic changes toward HIV-1, viral adaptive changes and genetic evolution

In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

“…Viruses isolated from the subsequent serial passages at different stages of infection were subjected to sequence analysis to identify and ascertain if any common changes could be found among these viruses given their shared ancestry. These studies also recapitulated some key aspects of cross-species transmission that we described previously in humanized mice that centered on SIVcpz and SIVsm to shed light on the origins of HIV-1 and HIV-2 from these respective progenitor viruses (3,4,48,50). Of the key observations from this present study, one was that both SIVmac239 and SIV B670 were readily able to infect hu-mice (Figures 1A,B).…”

“…Overall, relative to SIVmac239 and SIVhu, SIV B670 accumulated the largest number of nonsynonymous mutations with corresponding amino acid changes throughout the viral genome (Figure 3B, Table 2). The majority of these changes were found in the 3 ′ end of the viral genome similar to that found in previous studies on SIVsm and SIVcpz in hu-mouse studies (3,37,(48)(49)(50). Interestingly, one of the most striking features amongst the three passaged viruses was the mutation at residue 216 in Gag that appeared within all three different strains of viruses in a highly conserved part of the genome (26,53).…”

“…The SIVmac239 molecular clone plasmid was transfected into 293T cells, and the viral supernatant was concentrated using ultracentrifugation as described previously (39,50). A small aliquot from ultracentrifugation was set aside for a functional titer in TZM-bl reporter cells as previously described (50,87,88).…”

“…Both the models permit HIV infection due to the presence of full immune cell repertoire and have been used widely to investigate areas such as HIV pathogenesis, transmission, and latency (33,35,(44)(45)(46)(47). We previously used the hu-mouse model as a human surrogate system to dissect various aspects of the initial crossspecies transmission of SIV chimpanzee virus (SIVcpz) to the human giving rise to HIV-1 and the SIVsm progenitor virus in giving rise to HIV-2 (3,4,39,(48)(49)(50). These studies provided important insights into the important genetic changes these progenitor viruses had to undergo to quickly adapt to the human host and also shed light on the gradual genetic changes that arose as the viruses were serially passaged multiple times using this system.…”

Advances in Humanized Mouse Models to Improve Understanding of HIV-1 Pathogenesis and Immune Responses

“…An older, yet similar model without the NOD background termed Rag1 null Il2rg null or Rag2 null Il2rg null (DKO) mice (also known as BRG mice) ( 11 , 66 ), also demonstrated susceptibility to both R5- and X4-tropic variants of HIV-1 via vaginal and rectal mucosal transmission with insights on therapy efficacy, latency and chronic infection ( 24 – 26 , 67 , 68 ). Furthermore, hu-DKO/hu-BRG mice have greatly contributed to cross-species transmission and viral evolution investigations ( 69 , 70 ), as well as the development of Hu-mice based viral outgrowth assays to further the understanding of HIV latency ( 71 , 72 ). Successful mucosal infection in hu-DKO and hu-NRG mice best models natural human routes of HIV-1 transmission and allows studies of microbiota alteration ( 65 ) and topical pre-exposure prophylaxis (PrEP) ( 67 , 73 – 76 ).…”