Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8 ⁺ T cells

Abstract

The functional properties of circulating CD8+ T cells have been associated with immune control of HIV. However, viral replication occurs predominantly in secondary lymphoid tissues, such as lymph nodes (LNs). We used an integrated single-cell approach to characterize effective HIV-specific CD8+ T cell responses in the LNs of elite controllers (ECs), defined as individuals who suppress viral replication in the absence of antiretroviral therapy (ART). Higher frequencies of total memory and follicle-homing HIV-specific CD8+ T cells were detected in the LNs of ECs compared with the LNs of chronic progressors (CPs) who were not receiving ART. Moreover, HIV-specific CD8+ T cells potently suppressed viral replication without demonstrable cytolytic activity in the LNs of ECs, which harbored substantially lower amounts of CD4+ T cell–associated HIV DNA and RNA compared with the LNs of CPs. Single-cell RNA sequencing analyses further revealed a distinct transcriptional signature among HIV-specific CD8+ T cells from the LNs of ECs, typified by the down-regulation of inhibitory receptors and cytolytic molecules and the up-regulation of multiple cytokines, predicted secreted factors, and components of the protein translation machinery. Collectively, these results provide a mechanistic framework to expedite the identification of novel antiviral factors, highlighting a potential role for the localized deployment of noncytolytic functions as a determinant of immune efficacy against HIV.

The identity of human tissue-emigrant CD8+T cells

“…Intravascular HIV-specific CD8 + T cells in individuals with chronic progressive disease typically express a transitional memory phenotype (CCR7 − CD27 + CD45RA − ), which has generally been associated with functional exhaustion and defective maturation (Buggert et al, 2014;Champagne et al, 2001). In the context of our data, this phenotype might instead define tissue-trafficking cells, which could potentially access virally infected targets in LTs and NLTs (Buggert et al, 2018;Nguyen et al, 2019;Reuter et al, 2017). We also found that functionally and phenotypically distinct virusspecific CD8 + T cells were clonotypically related in blood and TDL.…”

“…In this scenario, cytolytic CD8 + T cells would reside in the bloodstream under physiological conditions, acting as a reservoir that could be mobilized rapidly in response to infection, inflammation, or injury anywhere in the body, akin to neutrophils. Previous studies have shown that CD8 + T cells loaded with perforin and serine proteases infiltrate tissue sites of pathology in many autoimmune diseases, cancers, and chronic infections (Boschetti et al, 2016;Duhen et al, 2018;Nguyen et al, 2019;Reuter et al, 2017;Strioga et al, 2011). However, most of these anatomically discrete cell populations were locally induced or constitutively resident, in contrast to non-resident cytolytic CD8 + T cells (CD69 − CX3CR1 + ) derived from the intravascular circulation (Buggert et al, 2018;Duhen et al, 2018).…”

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

“…For example, both the Mamu-B*08 allele [68] and the Mamu-B*17 allele [69] are associated with better immune control of SIV in rhesus macaques. Beyond MHC expression, there is also evidence that CD8 + T cells of human elite controllers have transcriptional signatures that favor cytokine expression over cytolytic functions, as compared to CD8 + T cells from chronic progressors [70]. Mechanisms behind elite control of SIV/HIV still need to be elucidated by further experimental and modeling studies.…”

Assessment of HIV-1 integration in tissues and subsets across infection stages

“…PBMCs and LNMCs were prepared as previously described ( 62 ). All cells were cryopreserved before being shipped on dry ice for experimental studies.…”