Olga Rivera Ballesteros(1) and Marcus Buggert(1).

Affiliates

1. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

Abstract

Background
Human immunodeficiency virus (HIV) is incurable due to a persistent latent reservoir that, in part, is thought to be harboured in Tfh CD4+ T cells in lymphoid tissues. We and others have described that follicular CD8+ T cells possess the ability to gain access to these reservoirs in lymph nodes. In this study, we aim to understand the distribution and function of follicular HIV-specific CD8+ T cells in the gastrointestinal (GI) tract, which will provide insights to harness this population for functional cure studies of HIV infection.
Recent data indicate that CTLs (cytolytic CD8+ T cells) appear unable to target the HIV reservoir, potentially through the lack of the B cell follicle homing marker CXCR5. Hence, a population of CXCR5+ CD8+ T cells (fCD8+ T cells) has gained interest. The overall role of fCD8+ T cells remains unclear, but previous studies have correlated fCD8+ T cells with increased control of HIV infection, and differentiation into short-lived cells with effector functions to kill virus-infected cells. However, most studies have been conducted on peripheral blood, despite HIV largely replicates and persists within B cell follicles in the GI tract. We hypothesize that an efficient anti-HIV response correlates to high frequencies of HIV-specific CXCR5+CD8 T cells with potent cytotoxic functions in the gut of infected individuals.

Methods
This project relies on a unique cohort of gut samples, including colonoscopies from five different sites (transverse, sigmoid, rectum, cecum, ileum) and matched blood from HIV infected (on and without ART) and uninfected subjects. A large flow cytometry panel with MHC-I restricted HIV tetramers allows us to dissect the phenotype of HIV-specific cells, focusing on cytotoxicity, activation, memory, tissue residence, and inhibitory signatures.

Results
Our results demonstrate that many fCD8+ T cells exist in the GI tract. We are currently exploring the phenotypic signatures, such as memory differentiation, cytotoxic potential, and exhaustion features within HIV-specific subsets. Within the CD4+ T cell compartment, we also find that some memory CD4+ T cells are co-expressing CCR5 and CXCR5. Knowing that CCR5 on CD4+ T cells is the main target for viral entry, it is important to examine this subset and its potential interaction with fCD8+ T cells.

Conclusions
These findings will clarify the functionality of fCD8+ T cells in the GI tract and provide insights on their potential association with a better outcome in HIV disease.