HIV remodels germinal centers through T follicular helper cell loss

T follicular helper cells (Tfh) within germinal centers are among the most permissive cells for HIV infection and serve as a critical part of the viral reservoir. Given the key role of Tfh in affinity maturation and the production of plasma cells and memory B cells, an understanding of this critical viral reservoir is fundamental not only for cure strategies but also for understanding immunodeficiency in people living with HIV (PLWH). Using rare clinical specimens from PLWH, we demonstrate that HIV causes both a change in the cellular composition of germinal centers and changes in their overall architecture in ways that are consistent with the immunodeficiency seen in PLWH, independent of their CD4 count. We note a significant decrease in the number of GC Tfh cells and an increase in the number of follicular CD8 T cells in lymphoid tissues obtained from PLWH. Our data further show that GC size is decreased both by HIV and with increased age. Single-cell RNA sequencing data demonstrate that HIV acutely decreases the expression of Tfh B-cell support pathways and disrupts Tfh expression of cell trafficking receptors. Additionally, in a lymphoid organoid model of acute infection that forms GC-like structures, these findings are recapitulated, suggesting that New Approach Methodologies could be germane to understanding the impact of HIV on the reservoir and immunodeficiency. This study describes previously undocumented remodeling of the germinal center niche in PLWH, providing insight into the immune microenvironment of a key HIV reservoir that may help inform future cure strategies.

Human immunodeficiency virus (HIV) is a chronic viral infection that affects more than 40 million people worldwide. Even with antiretroviral therapy, people living with HIV remain at increased risk for a variety of comorbidities and exhibit persistent immune dysfunction that may worsen with age. Understanding how HIV impacts key immune structures such as germinal centers is important for preventing or reversing these effects. This study reveals changes in germinal center composition and cellular function, including decreased T follicular helper cells and germinal center size, that may contribute to persistent immune dysfunction in people living with HIV. Our findings provide new insight into how HIV alters the lymphoid tissue microenvironment despite antiretroviral therapy and establish a lymphoid organoid model for investigating these changes, which may help identify new strategies to reduce HIV-associated morbidity.