PT  - JOURNAL ARTICLE
AU  - Austin, James W.
AU  - Buckner, Clarisa M.
AU  - Kardava, Lela
AU  - Wang, Wei
AU  - Zhang, Xiaozhen
AU  - Melson, Valerie A.
AU  - Swanson, Ryan G.
AU  - Martins, Andrew J.
AU  - Zhou, Julian Q.
AU  - Hoehn, Kenneth B.
AU  - Fisk, J. Nicholas
AU  - Dimopoulos, Yiannis
AU  - Chassiakos, Alexander
AU  - O’Dell, Sijy
AU  - Smelkinson, Margery G.
AU  - Seamon, Catherine A.
AU  - Kwan, Richard W.
AU  - Sneller, Michael C.
AU  - Pittaluga, Stefania
AU  - Doria-Rose, Nicole A.
AU  - McDermott, Adrian
AU  - Li, Yuxing
AU  - Chun, Tae-Wook
AU  - Kleinstein, Steven H.
AU  - Tsang, John S.
AU  - Petrovas, Constantinos
AU  - Moir, Susan
TI  - Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation
AID  - 10.1126/scitranslmed.aax0904
DP  - 2019 Nov 27
TA  - Science Translational Medicine
PG  - eaax0904
VI  - 11
IP  - 520
4099  - http://stm.sciencemag.org/content/11/520/eaax0904.short
4100  - http://stm.sciencemag.org/content/11/520/eaax0904.full
AB  - Despite the presence of abundant and persistent antigen, chronic infections such as HIV often do not induce protective antibody responses. Memory B cells from people chronically infected with HIV have previously been reported to express the transcription factor T-bet. Austin et al. observed that T-bethi memory B cells were in the lymph nodes but not localized to germinal centers, where high-affinity antibody responses develop. Although clonally related to germinal center B cells, these T-bethi memory B cells had a lower frequency of somatic hypermutation and reduced capacity to neutralize HIV in vitro. Exclusion of T-bethi memory cells from germinal centers may be one mechanism contributing to the lack of a protective antibody response in most HIV infections.Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet–expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome. Confocal microscopy and quantitative imaging revealed that T-bethi B cells in LN of HIV-infected chronically viremic individuals distinctly accumulated outside germinal centers (GC), which are critical for optimal antibody responses. In single-cell analyses, LN T-bethi B cells of HIV-infected individuals were almost exclusively found among CD19hi MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19hiT-bethi MBC and displayed a distinct transcriptome, with features similar to CD19hiT-bethi MBC in blood and LN GC B cells (GCBC). LN CD19hiT-bethi MBC were also related to GCBC by B cell receptor (BCR)–based phylogenetic linkage but had lower BCR mutation frequencies and reduced HIV-neutralizing capacity, consistent with diminished participation in GC-mediated affinity selection. Thus, in the setting of chronic immune activation associated with HIV viremia, failure of HIV-specific B cells to enter or remain in GC may help explain the rarity of high-affinity protective antibodies.