Antigenic molecular mimicry in viral-mediated protection from cancer: the HIV case

Abstract

Background: People living with HIV/AIDS (PLWHA) show a reduced incidence for three cancer types, namely breast, prostate and colon cancers. In the present study, we assessed whether a molecular mimicry between HIV epitopes and tumor associated antigens and, consequently, a T cell cross-reactivity could provide an explanation for such an epidemiological evidence.

Methods: Homology between published TAAs and non-self HIV-derived epitopes have been assessed by BLAST homology. Structural analyses have been performed by bioinformatics tools. Immunological validation of CD8⁺ T cell cross-reactivity has been evaluated ex vivo by tetramer staining.

Findings: Sequence homologies between multiple TAAs and HIV epitopes have been found. High structural similarities between the paired TAAs and HIV epitopes as well as comparable patterns of contact with HLA and TCR α and β chains have been observed. Furthermore, cross-reacting CD8⁺ T cells have been identified.

Interpretation: This is the first study showing a molecular mimicry between HIV antigens an TAAs identified in breast, prostate and colon cancers. Therefore, it is highly reasonable that memory CD8⁺ T cells elicited during the HIV infection may play a key role in controlling development and progression of such cancers in the PLWHA lifetime. This represents the first demonstration ever that a viral infection may induce a natural "preventive" anti-cancer memory T cells, with highly relevant implications beyond the HIV infection.

Keywords: Breast cancer; Colon cancer; Cross-reactive T cells; HIV-1; Molecular mimicry; Tumor-associated antigens; Viral antigens.

Fig. 1

Predicted tumor antigens. Cumulative number of predicted antigens from all cancer-specific proteins identified in each tumor, listed by cancer (A). Cumulative predicted affinity of predicted antigens from all cancer-specific proteins identified in each tumor, listed by cancer (B) and by HLA allele (C)

Fig. 2

Predicted HIV-1 peptides homologous to tumor antigens. Cumulative number of HIV-1 predicted antigens homologous to TAAs from all cancer-specific proteins identified in each tumor (A). Number of HIV-1 predicted antigens associated to each HLA allele homologous to TAAs from all cancer-specific proteins identified in each tumor, listed by cancer (B). Number of HIV-1 predicted antigens associated to each HLA allele homologous to TAAs from each cancer-specific proteins identified in each tumor, listed by protein (C). Cumulative predicted affinity of HIV-1 predicted antigens listed by HLA allele (D)

Fig. 3

Experimental binding of TAAs and HIV-1 paired peptides to HLA-A*0201. Binding to HLA-A*0201 molecule and relative stability was assessed in TAP-deficient T2 cells loaded with the indicated peptides. Mean fluorescence intensity at flow cytometer indicates binding levels of peptides to HLA molecules (A). Decay of mean fluorescence intensity over time indicates stability of the peptide binding to the HLA molecule, expressed as absolute values (B) or percentage of values (C)

Fig. 4

Predicted 3D conformation of paired peptides. The conformation of the TAAs and paired HIV-1 antigens and consensus bound to the indicated HLA molecules is shown. The prediction was performed using as template structure peptides crystallized with indicated HLA molecules. Only for HLA-A*02:01, HLA-A*01:01 and HLA-B*07:02 information about the β2 microglobulin, the α and β chains of the T cell receptor (TCR) were available (PDB https://www.rcsb.org/structure/1AO7, 5BRZ, 6VMX). Green areas = contact points with HLA molecule; Blue areas = contact points with the TCR α chain; Violet areas = contact points with the TCR β chain

Fig. 5

Evaluation of cross-reactive CD8 + T cells. pMHC directed expansion of T cells validated the presence of T cells specific for each paired TAA and viral epitopes are shown. Frequencies of pMHC multimer specific T cells out of total CD3⁺ CD8⁺ are displayed. Data from individual HIV patients and healthy donors are shown (A–D). Cumulative data from all HIV patients and all healthy donors are shown (E–L)