Identification of NK Cell Subpopulations That Differentiate HIV-Infected Subject Cohorts with Diverse Levels of Virus Control

Abstract

HIV infection is controlled immunologically in a small subset of infected individuals without antiretroviral therapy (ART), though the mechanism of control is unclear. CD8 ϩ T cells are a critical component of HIV control in many immunological controllers. NK cells are also believed to have a role in controlling HIV infection, though their role is less well characterized. We used mass cytometry to simultaneously measure the levels of expression of 24 surface markers on peripheral NK cells from HIV-infected subjects with various degrees of HIV natural control; we then used machine learning to identify NK cell subpopulations that differentiate HIV controllers from noncontrollers. Using CITRUS (cluster identification, characterization, and regression), we identified 3 NK cell subpopulations that differentiated subjects with chronic HIV viremia (viremic noncontrollers [VNC]) from individuals with undetectable HIV viremia without ART (elite controllers [EC]). In a parallel approach, we identified 11 NK cell subpopulations that differentiated HIV-infected subject groups using k-means clustering after dimensionality reduction by t-neighbor stochastic neighbor embedding (tSNE) or linear discriminant analysis (LDA). Among these additional 11 subpopulations, the frequencies of 5 correlated with HIV DNA levels; importantly, significance was retained in 2 subpopulations in analyses that included only cohorts without detectable viremia. By comparing the surface marker expression patterns of all identified subpopulations, we revealed that the CD11b ϩ CD57 Ϫ CD161 ϩ Siglec-7 ϩ subpopulation of CD56 dim CD16 ϩ NK cells are more abundant in EC and HIV-negative controls than in VNC and that the frequency of these cells correlated with HIV DNA levels. We hypothesize that this population may have a role in immunological control of HIV infection. IMPORTANCE HIV infection results in the establishment of a stable reservoir of latently infected cells; ART is usually required to keep viral replication under control and disease progression at bay, though a small subset of HIV-infected subjects can control HIV infection without ART through immunological mechanisms. In this study, we sought to identify subpopulations of NK cells that may be involved in the natural immunological control of HIV infection. We used mass cytometry to measure surface marker expression on peripheral NK cells. Using two distinct semisupervised machine learning approaches, we identified a CD11b ϩ CD57 Ϫ CD161 ϩ Siglec-7 ϩ subpopulation of CD56 dim CD16 ϩ NK cells that differentiates HIV controllers from noncontrollers. These cells can be sorted out for future functional studies to assess their potential role in the immunological control of HIV infection.

Timing of Antiretroviral Therapy Initiation Determines Rectal Natural Killer Cell Populations

“…9,20,23 In addition, a subset of CD56 dim CD16 + cells expressing CD11b and CD161 but not CD57 or Siglec-7 may contribute to virologic control, potentially by a higher frequency of degranulation, as they are more common in elite controllers than viremic persons. 24 The correlation of higher frequencies of CD56 dim CD16 bright cells in the rectal tissue with higher circulating CD4 + T cell counts in our study would be consistent with this hypothesis. As this population also correlates with a higher rectal HIV-1 reservoir, it is tempting to speculate that these populations are responding to the increased reservoir.…”

“…10,19,20,26 Indeed, CD56 -CD16 bright cells are rare in the absence of disease, 10,22 but CD56 -CD16 + NK cells are increased in viremic persons compared with HIV-negative controls. 24 Consistent with this observation, we found that this population tended to be higher in the rectum of people who were not taking ART compared with those who initiated ART in chronic HIV-1 infection.…”

“…We did not have sufficient samples to further characterize CD56 bright cells, such as by evaluating NK cell receptors or surface markers such as CD11b and CD161 that distinguish subsets of CD56 bright cells that differentiate viremic from treated people with HIV. 24 The inverse association of rectal CD4 Tscm with circulating cytotoxic NK cells raises the question of whether these CD4 Tscm persist because of insufficient control by NK cells. In contrast, the direct association of rectal CD8 Tscm with rectal cytokine-producing and cytotoxic NK cells may reflect an overall environment supporting HIV-1 control.…”

Immunologic perturbations in severe COVID-19/SARS-CoV-2 infection

“…1), we further assessed the phenotype of innate immune cells. CD161 has been reported to be a marker of inflammatory monocytes and NK cells (32)(33)(34). Despite having observed a decreased frequency of CD161+ CD8 T cells ( Fig.…”

Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection

“…5C-E), given the multi-faceted role of NK cells in viral control 64 . Assaying cells from controllers in-vitro showed that NK cells were equivalent to CD8 + T cells in inhibiting viral replication 95 ; however recent work has demonstrated CD11b + CD57 - CD161 + Siglec-7 + NK cells to be more abundant in elite controllers compared to those who progress 96 . The proliferating NK cells measured here also express high levels of CD161 ( KLRB1 ), associated with the production of IFN- γ in response to IL-12 and IL-18 97 .…”