Coreceptor switch in R5-tropic simian/human immunodeficiency virus-infected macaques

Area of Science:

• Virology
• Immunology
• Pathogenesis

Background:

• The shift from CCR5 (R5) to CXCR4 (X4) coreceptor usage in human immunodeficiency virus type 1 (HIV-1) subtype B is observed in about 50% of individuals as disease progresses.
• The underlying mechanisms for this coreceptor switch remain incompletely understood, with proposed factors including target cell availability and immune evasion.

Purpose of the Study:

• To investigate the emergence of CXCR4 (X4)-tropic virus in a nonhuman primate model infected with R5-tropic simian/human immunodeficiency virus (SHIV).
• To determine if coreceptor switch occurs in a relevant animal model for HIV/AIDS research.
• To explore the evolutionary pathways and immunological factors influencing HIV-1 coreceptor tropism switch.

Main Methods:

• Infection of rhesus macaques (RM) with R5-tropic SHIV.
• Monitoring of viral coreceptor usage and envelope sequence evolution.
• Analysis of viral neutralization sensitivity and host antiviral immune responses.

Main Results:

• Demonstrated the emergence of X4 virus in an R5-SHIV infected rhesus macaque, validating a nonhuman primate model for HIV-1 coreceptor switch.
• Identified envelope V3 loop sequence changes associated with the switch to CXCR4 usage, mirroring those observed in humans.
• The emerging X4 virus exhibited increased neutralization sensitivity compared to the initial R5 virus.
• X4 virus evolution occurred in an animal with suppressed detectable virus-specific antibodies and low cellular immunity.

Conclusions:

• The R5-to-X4 evolution pathways for human immunodeficiency virus type 1 appear conserved between humans and nonhuman primates.
• The findings support a model where antiviral immunity plays an inhibitory role in modulating HIV-1 coreceptor tropism.
• Coreceptor tropism switch in HIV-1 can be studied effectively in a rhesus macaque model.