# Multifaceted B cell response to transient HIV viremia in elite controllers

## TL;DR

This study explores how B cells respond to a brief HIV virus flare in people who naturally control the virus, revealing new insights into B cell diversity and function.

## Contribution

The study identifies distinct B cell subsets and their responses to transient HIV viremia in elite controllers using multi-omics and single-cell sequencing.

## Key findings

- TLM B cells showed lower mutation and diversity compared to other memory B cells.
- A transient HIV viremia increased Env-reactive IgG and non-TLM B cells.
- Two distinct TLM subsets were identified, following different B cell pathways.

## Abstract

Chronic HIV infection drives B cell dysfunction associated with the accumulation of tissue-like memory (TLMs) and activated memory B cells (MBCs) but decline in resting memory B cells. TLMs express multiple inhibitory receptors and lack response to soluble antigens. However, their origin and the mechanisms driving their expansion in HIV infection remain unclear. From bulk heavy chain BCR sequencing of MBC subsets from 5 PLWH with no detectable viremia, we hypothesized that TLMs (CD21- CD27- B cells) were significantly less mutated but also less diverse than other MBCs, suggesting an enrichment for innate-like B cells or that they belong to a less mature subset. Subsequent detailed multi-omics study of an immune response to a transient HIV viremia in an elite controller demonstrated a functional increase in Env-reactive IgG and MBCs with non-TLM phenotype. Single-cell RNA/BCR sequencing of PBMCs enriched for B cells revealed an orchestrated TNF-α response followed by interferon-α and -γ responses across all B cell subsets. This study provides new insights into multifaceted functional B cell response to transient HIV viremia and highlights TLM heterogeneity.

HIV infection changes the proportions and types of immune cells in the blood. T cells are affected because they are directly infected by HIV. However, how HIV alters the traits of B cells, in particular a subset called tissue-like memory B cells, is not fully understood. These cells have been purported to arise due to excessive viral stimulation and be in an exhausted state unable to perform normal B cell functions. However, tissue-like memory B cells have also been found in uninfected controls post-vaccination and may be a normal stepping stone in the trajectory of a B cell towards becoming an antibody-secreting cell. In this study we investigated the antibody response and gene expression profiles of tissue-like memory B cells in an individual who had spontaneous control of HIV (in the absence of treatment) but experienced a transient episode of detectable virus in their blood. We saw no increase in tissue-like memory B cells in response to this viral episode and no enrichment for virus-specific tissue-like memory B cells. Our results suggested these cells were formed in an interferon-driven rather than antigen-driven process, and we identified two distinct subsets of tissue-like-memory B cells following distinct B cell pathways.