2017
DOI: 10.1016/j.coi.2017.06.004
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Immunological tolerance as a barrier to protective HIV humoral immunity

Abstract: HIV-1 infection typically eludes antibody control by our immune system and is not yet prevented by a vaccine. While many viral features contribute to this immune evasion, broadly neutralizing antibodies (bnAbs) against HIV-1 are often autoreactive and it has been suggested that immunological tolerance may restrict a neutralizing antibody response. Indeed, recent Ig knockin mouse studies have shown that bnAb-expressing B cells are largely censored by central tolerance in the bone marrow. However, the contributi… Show more

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Cited by 16 publications
(16 citation statements)
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“…The SIVmac239 Env protein was truncated at E767, and the nef gene contained a 6-bp deletion corresponding to Nef amino acids 239-240 to abrogate down-regulation of MHC-I (16). The tat gene also encoded a L35Q substitution to inactivate the immunodominant Mamu-A*01-restricted Tat [28][29][30][31][32][33][34][35] SL8 epitope (17). Because subdominant CD8 + T cell responses can be actively suppressed by dominant CD8 + T cell responses in the context of rDNA immunization (18), the rationale for the Tat L35Q change in the rDNA-SIVnfl vector was to broaden the repertoire of vaccine-induced SIV-specific CD8 + T cells in the Mamu-A*01 + vaccinees in the present study.…”
Section: Resultsmentioning
confidence: 99%
“…The SIVmac239 Env protein was truncated at E767, and the nef gene contained a 6-bp deletion corresponding to Nef amino acids 239-240 to abrogate down-regulation of MHC-I (16). The tat gene also encoded a L35Q substitution to inactivate the immunodominant Mamu-A*01-restricted Tat [28][29][30][31][32][33][34][35] SL8 epitope (17). Because subdominant CD8 + T cell responses can be actively suppressed by dominant CD8 + T cell responses in the context of rDNA immunization (18), the rationale for the Tat L35Q change in the rDNA-SIVnfl vector was to broaden the repertoire of vaccine-induced SIV-specific CD8 + T cells in the Mamu-A*01 + vaccinees in the present study.…”
Section: Resultsmentioning
confidence: 99%
“…One unresolved aspect is to what extent inflammation and non-cognate T cell help can drive promiscuous recruitment of autoreactive B cells into a GC reaction. It is well-documented that viral infection can lead to collateral autoantibodies (28) and, based on analyses of somatic hypermutation, that this can proceed through a canonical GC (29). Additionally, antibodies that are generated against pathogens are frequently polyreactive and cross-react with endogenous self-antigens (21).…”
Section: Discussionmentioning
confidence: 99%
“…Additionally, antibodies that are generated against pathogens are frequently polyreactive and cross-react with endogenous self-antigens (21). An oft-picked example is that antibodies neutralizing HIV are derived from germline autoreactive precursors (29), indicating that self-reactive B cell recruitment into a GC is a rare but biologically meaningful event. In a recent study (30), infection with γ-herpesvirus elicited affinity-matured autoantibodies that did not have germline autoreactivity, leading to the inference that self-binding had been acquired and positively selected inside GC.…”
Section: Discussionmentioning
confidence: 99%
“…74,75 Glycans are suitable antibody targets from a biophysical perspective, but self-glycans elicit so little antibody because they are displayed on the surface of every cell and hence will be potent inducers of B cell tolerance checkpoints. 76 Given the conundrum of generating holes in the immune repertoire, retaining weakly self-reactive antibodies on anergic B cells F I G U R E 1 Rationale for immune system being based on a nascent repertoire of polyspecific B cells capable of clonal redemption. Top schematic illustrates a scenario where V(D)J recombination creates a B cell repertoire bearing antibodies with exquisite monospecificity.…”
Section: Anerg I C Cell S a S Provider S Of Protec Tive P Olyre Ac mentioning
confidence: 99%