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

Area of Science:

• Virology
• Genetics
• Immunology

Background:

• The cross-species transmission of simian immunodeficiency virus (SIVcpz) to humans, leading to the emergence of human immunodeficiency virus type 1 (HIV-1), is not fully understood.
• Understanding the initial genetic changes and adaptation of SIVcpz during human infection is crucial for comprehending HIV-1 origins and evolution.

Purpose of the Study:

• To simulate the initial transmission of SIVcpz to humans using a humanized mouse model.
• To investigate the viral evolution, pathogenicity, and genetic alterations of SIVcpz during serial passages in vivo.
• To identify potential genomic changes in SIVcpz that may have occurred during the early stages of human infection.

Main Methods:

• Serial passage of three SIVcpz strains (LB715, MB897, EK505) in humanized mice.
• Monitoring of viral loads and CD4+ T cell counts throughout the passages.
• Sequencing of viral genomes at different time points to identify genetic variants.

Main Results:

• SIVcpz strains readily infected humanized mice, establishing chronic viremia.
• Viral loads increased to higher set-points, and CD4+ T cell decline became more pronounced after the second passage, indicating adaptation and increased pathogenicity.
• Sequencing revealed numerous novel non-synonymous variants across the viral genome, including gag, pol, env, and nef genes.

Conclusions:

• Humanized mice effectively model SIVcpz adaptation and increased pathogenicity following cross-species transmission.
• The study identified significant genetic changes in SIVcpz during early in vivo evolution, providing insights into potential HIV-1 progenitor alterations.
• These findings contribute to understanding the genomic landscape of SIVcpz during the initial phase of human infection and subsequent spread.