Experimental Adaptive Evolution of Simian Immunodeficiency Virus SIVcpz to Pandemic Human Immunodeficiency Virus Type 1 by Using a Humanized Mouse Model

Abstract

Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, originated from simian immunodeficiency virus from chimpanzees (SIVcpz), the precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz strains (MB897, EK505, and MT145), four pandemic HIV-1 strains (NL4-3, NLCSFV3, JRCSF, and AD8), and two nonpandemic HIV-1 strains (YBF30 and DJO0131). Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a peak viral load comparable to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strain EK505 or MT145 as well as nonpandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is preadapted to humans, unlike the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation in , a G413R substitution in gp120. The infectivity of the gp120 G413R mutant of MB897 was significantly higher than that of parental MB897. Furthermore, we demonstrated that the gp120 G413R mutant of MB897 augments the capacity for viral replication in both cell cultures and humanized mice. Taken together, this is the first experimental investigation to use an animal model to demonstrate a gain-of-function evolution of SIVcpz into pandemic HIV-1. From the mid-20th century, humans have been exposed to the menace of infectious viral diseases, such as severe acute respiratory syndrome coronavirus, Ebola virus, and Zika virus. These outbreaks of emerging/reemerging viruses can be triggered by cross-species viral transmission from wild animals to humans, or zoonoses. HIV-1, the causative agent of AIDS, emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzees, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. Here, by using a hematopoietic stem cell-transplanted humanized-mouse model, we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, preadapted to infect humans over other SIVcpz strains. We further demonstrate a gain-of-function evolution of SIVcpz in infected humanized mice. Our study reveals that pandemic HIV-1 has emerged through at least two steps: preadaptation and subsequent gain-of-function mutations.

A glycan shield on chimpanzee CD4 protects against infection by primate lentiviruses (HIV/SIV)

“…3 D and E). This is consistent with previous reports that SIVcpz can utilize human CD4 (45)(46)(47)(48), collectively supporting the idea that human CD4 was not a barrier in either of the zoonotic transmissions leading to HIV-1 group M and group N.…”

Coronavirus infections and immune responses

“…MERS‐CoV and SARS‐CoV are β‐coronaviruses that can cause fatal lower respiratory tract infections and extrapulmonary manifestations 70–72 . T cells, CD4+ T cells, and CD8+ T cells particularly play a significant antiviral role by balancing the combat against pathogens and the risk of developing autoimmunity or overwhelming inflammation 73 .…”

Mimicking SIV chimpanzee viral evolution toward HIV‐1 during cross‐species transmission

“…Here, we experimentally simulated the human exposures of SIVcpzLB715 and serial propagation in multiple human immune environments to determine the mutations that led to the generation of the pathogenic HIV‐1 Group M virus. We used humanized hematopoietic stem cell (hu‐HSC) mice harboring a complete repertoire of human immune cells susceptible to SIV and HIV infection to model these genetic adaptions 8‐15 . SIVcpzLB715 was used to infect a cohort of hu‐HSC mice and passaged into a second generation of mice (Figure 1A ) .…”