Efficient SIVcpz replication in human lymphoid tissue requires viral matrix protein adaptation

Area of Science:

• Virology
• Immunology
• Evolutionary Biology

Background:

• Simian immunodeficiency viruses (SIVs) have crossed the species barrier from apes to humans multiple times, leading to the AIDS pandemic.
• The precursor to pandemic HIV-1, SIVcpz, infects chimpanzees, but its ability to replicate in human lymphoid tissues (HLTs) was previously unknown.

Purpose of the Study:

• To investigate the replication capacity of SIVcpz strains in human lymphoid tissues.
• To identify viral factors that may have facilitated the cross-species transmission of SIVcpz to humans, leading to HIV-1 emergence.

Main Methods:

• Replication of SIVcpz strains from two chimpanzee subspecies was assessed in human tonsillary explant cultures (HLTs).
• Mutations, specifically a human-specific adaptation at position 30 in the Gag matrix protein, were introduced to evaluate their impact on viral replication in HLTs and chimpanzee CD4(+) T cells.

Main Results:

• Naturally occurring SIVcpz strains replicated at low titers in human tonsillary explant cultures.
• A specific adaptation (Arg or Lys at position 30) in the viral Gag matrix protein significantly enhanced SIVcpz replication in HLTs.
• The same mutation that enhanced human replication reduced viral replication in chimpanzee-derived CD4(+) T cells, indicating host-specific adaptation.

Conclusions:

• Naturally occurring SIVcpz strains can infect human lymphoid tissues, the primary site of HIV-1 replication.
• Efficient SIVcpz replication in humans requires host-specific adaptations, particularly within the Gag matrix protein.
• The Gag matrix protein is a critical determinant of SIVcpz replication fitness in humans, playing a significant role in the emergence of HIV/AIDS.