Abstract
Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a special challenge to the prevention and treatment of tuberculosis and HIV/AIDS. Adoptive transfer of high-affinity T cell receptor (TCR) gene-modified T cells against MTB and HIV antigens is a promising approach to treating MTB/HIV coinfected patients whose cellular immunity is obviously disordered. We have previously successfully identified that a bispecific TCR screened out from peripheral blood mononuclear cells of a HLA-A*0201+ healthy individual using the complementarity determining region 3 (CDR3) spectratype analysis recognizes both MTB Ag85B199–207 and HIV-1 Env120–128 peptide. However, it has not been known how residues on CDR3 loops, which have been shown to play a leading role in antigen binding and specificity contribute to the bispecific TCR contact with the peptide–major histocompatibility complex (MHC) complexes. In this study, we provided an extensive investigation of residues in the predicted CDR3 of the bispecific TCR beta (β) chain using alanine scanning mutagenesis. Our data showed that three of the five substituted residues (G115A, T116A, A117G) in CDR3β of the bispecific TCR caused a significantly diminished T cell response to antigen, whereas the remaining two substituted residues (D114A, S118A) resulted in completely eliminated response, thus identifying the two residues that were particularly critical for the recognition of peptide–MHC in the bispecific TCR. These findings will provide an imperative foundation for generating an improved high-affinity bispecific TCR for use in T cell adoptive immunotherapy for MTB/HIV coinfected individuals.
Highlights
Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a massive challenge to the prevention and treatment of tuberculosis (TB) and HIV/AIDS
The MTB Ag85B199–207 and HIV-1 Env120–128 bispecific T cell receptor (TCR) α17 and β15 genes were identified by TCR complementarity determining region 3 (CDR3) spectratype analysis (Figure 1A) as described in our previous study [27]
We demonstrated the importance of amino acids (AAs) in the predicted CDR3 of the bispecific TCR β-chain in recognition of MTB
Summary
Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a massive challenge to the prevention and treatment of tuberculosis (TB) and HIV/AIDS. TB has an adverse impact on immune responses to HIV, which accelerates the course of disease from HIV infection to AIDS [1]. Among the estimated 10.4 million new TB cases in 2015, about 1.2 million (11%) were estimated to be HIV positive. Notwithstanding World Health Organization guidelines supporting long courses of concomitant anti-TB and antiretroviral therapies of the two diseases and urging more aggressive management, multiple problems such as potential drug interactions between rifampin and some kinds of antiretroviral drugs, cumulative drug toxicities, a high pill burden, the immune reconstitution inflammatory syndrome, and programmatic challenges still exist [3]. Development of new therapeutic options for MTB/HIV coinfection has become imperative
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