HLA tapasin independence: broader peptide repertoire and HIV control

Abstract

Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.

HLA polymorphism and tapasin independence influence outcomes of HIV and dengue virus infection

“…Importantly, findings from Bashirova et al (19) suggest that HLA tapasin independence not only influences immune responses by broadening the repertoire of antigenic peptides, also documented by other groups, but can significantly affect infectious disease outcomes. Ultimately, the discovery of the HLA allotypes and their lack of TD for peptide editing will have important practical implications in designing novel successful vaccines and immunotherapies against infectious diseases and cancer.…”

“…Of note is that these results were further validated using the influence of TD on viral load in an independent cohort of 4,306 individuals prior to initiation of antiretroviral therapy with longitudinal viral load measurements. More importantly, in a large cohort of HIV-infected individuals, the authors demonstrate that tapasin-independent HLA allotypes are associated with slower disease progression and lower viral load (19).…”

Polymorphisms in MHC class I molecules influence their interactions with components of the antigen processing and presentation pathway

“…There is a significant variability in how dependent MHC‐I allotypes are on the presence of TAP and tapasin for peptide acquisition and surface expression (Bashirova et al., 2020; Geng et al., 2018; Rizvi et al., 2014). The level of MHC‐I dependence on TAP and tapasin is correlated, which may be explained by the fact that both are integral to the PLC (Geng, Zaitouna, et al., 2018).…”

“…The level of MHC‐I dependence on TAP and tapasin is correlated, which may be explained by the fact that both are integral to the PLC (Geng, Zaitouna, et al., 2018). One notable example of a TAP‐ and tapasin‐independent allotype is HLA‐B*44:05, which does not show reduced surface expression on TAP‐deficient cells and has a low tapasin dependence score based on similar surface expression studies (Bashirova et al., 2020; Rizvi et al., 2014; Williams et al., 2002). Interestingly, the closely related allotype HLA‐B*44:02 is highly dependent on both TAP and tapasin.…”

“…Among HLA‐B allotypes, the presence of the Bw4 epitope shows a positive correlation with tapasin dependence, whereas the Bw6 epitope is associated with tapasin independence, but this epitope alone does not account for all of the variation in dependence across HLA‐Bs (Rizvi et al., 2014). A recent study has shown that across all MHC‐I allotypes, there is a wide range of tapasin dependence and that more tapasin‐independent allotypes present a broader peptide repertoire, possibly indicating an ability to acquire peptides outside the PLC in the absence of tapasin (Bashirova et al., 2020). This study also linked the overall tapasin dependence of an HLA complement to progression to AIDS in HIV‐positive individuals (Bashirova et al., 2020).…”