Human leukocyte antigen class I heavy chain–beta-2 microglobulin–HIV-1 peptide complex (HLA-I/B2M/HIV pMHC)

The Human leukocyte antigen class I heavy chain–beta-2 microglobulin–HIV-1 peptide complex (pMHC) is a heterotrimeric assembly essential for the cellular immune response against HIV-1 (UniProt: P01889, P61769). It consists of a polymorphic HLA class I heavy chain, a beta-2 microglobulin light chain, and an 8-10 amino acid peptide derived from HIV-1 proteins like Gag or Pol (PMID: 31534225). This complex is expressed on the surface of infected cells, where it serves as the primary ligand for the T-cell receptors (TCRs) of CD8+ cytotoxic T lymphocytes (NCBI: NBK27156). In HIV-1 infection, the virus often attempts to evade this recognition by downregulating HLA expression via the Nef protein, contributing to viral persistence (PMID: 11836371). Modern immunotherapeutic strategies, such as TCR-engineered T cells and Immune mobilizing monoclonal TCRs against cancer/infection (ImmTACs), specifically target these pMHC complexes to bypass viral evasion and eliminate the latent reservoir (PMID: 26305929). A prominent example is IMC-HIV, a bispecific molecule designed to redirect T cells to kill cells presenting HIV Gag peptides (Immunocore). Therapeutic development is complicated by the extreme polymorphism of HLA alleles and the high mutation rate of HIV-1, which can lead to epitope loss (PMID: 16113237). Furthermore, ensuring high specificity is critical to avoid off-target reactivity against similar self-peptides, which could lead to severe autoimmune-like toxicity (PMID: 23846135).

Other names

MHC class I–HIV peptide complexpMHC complex (HIV)HLA-A*02:01/HIV-1 Gag peptide complexHLA-I/B2M/peptide

Recognition of the specific peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-like antibodies to trigger targeted lysis of HIV-infected cells.