In people living with HIV (PLWH), B-cell immunity often remains impaired despite effective antiretroviral therapy (ART), resulting in suboptimal and less durable antibody responses. A major contributor to this dysfunction is the expansion and persistence of atypical B cells (atBCs), an antigen-experienced memory B-cell population associated with reduced responsiveness to stimulation and impaired HIV-specific antibody production. While atBC emergence during infection is linked to immune activation, their persistence during ART suggests that ongoing inflammatory signals actively sustain this dysfunctional state. BAFF (B-cell activating factor), a monocyte-derived regulator of B-cell survival that remains elevated in treated HIV, represents a strong candidate mediator of atBC persistence. However, whether monocyte-derived BAFF is sufficient to sustain atBC phenotypes during ART has not been directly tested, limiting the development of targeted strategies to reduce chronic immune activation and restore durable humoral immunity in PLWH.
The long-term goal of this work is to define therapeutically targetable mechanisms that sustain atBCs in chronic HIV. The objective of this pilot study is to determine whether monocyte-derived inflammatory signals induce atBC-associated features and whether BAFF supports their persistence, and to establish whether this pathway is operative in ART-treated HIV. Our central hypothesis is that inflammatory signals produced by activated monocytes promote atBC-associated phenotypes and that BAFF selectively supports survival and persistence of this activated subset. This hypothesis is supported by evidence that monocyte activation and BAFF remain elevated in treated HIV and by studies in chronic inflammatory diseases demonstrating that excess BAFF can sustain atBCs in vivo.
Aim 1 will assess whether monocyte-derived inflammatory cues contribute to atBC persistence in treated HIV. In Aim 1a, we will use a culture system to test whether inflammatory activation of monocytes from HIV-negative donors is sufficient to induce atBC-associated features in autologous B cells, and to define the contribution of BAFF to atBC persistence using BAFF neutralization. In Aim 1b, we will evaluate disease relevance by testing whether monocytes from ART-treated PLWH, without exogenous stimulation, generate conditioned media capable of inducing and sustaining atBC phenotypes in B cells from HIV-negative donors. Multiplex cytokine profiling will be used to link monocyte inflammatory cytokine production, including BAFF, to functional effects on B-cell phenotype and survival. Successful completion of this project will provide the basis for future NIH-funded studies aimed at reducing chronic inflammation, restoring B-cell homeostasis, and improving long-term antibody-mediated immunity in PLWH.
Project Summary provided by investigator.