Persistence of a Skewed Repertoire of NK Cells in People with HIV-1 on Long-Term Antiretroviral Therapy.

HIV-1 infection greatly alters the NK cell phenotypic and functional repertoire. This is highlighted by the expansion of a rare population of FcRγ- NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1-associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcRγ- memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1-4 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.

IL-18 Responsiveness Defines Limitations in Immune Help for Specialized FcRγ- NK Cells.

Despite being prolific innate killers, NK cells are also key helper cells in antiviral defense, influencing adaptive immune responses via interactions with dendritic cells (DCs). In addition to causing NK cell dysfunction, HIV-1 infection contributes to the expansion of a rare population of NK cells deficient in FcRγ (FcRγ-), an intracellular adaptor protein that associates with CD16. The implications of this inflated NK cell subset in treated HIV-1 infection remain unclear. In this study, we explored the helper function of human NK cells in chronic HIV-1 infection, with a particular focus on characterizing FcRγ- NK cells. Exposure of NK cells to innate DC-derived costimulatory factors triggered their helper activity, defined by their ability to produce IFN-γ and to drive the maturation of high IL-12-producing DCs. In this setting, however, FcRγ- NK cells were defective at producing the dominant DC-polarizing agent IFN-γ. The reduced responsiveness of FcRγ- NK cells to IL-18 in particular, which was attributable to impaired inducible expression of IL-18Rα, extended beyond an inability to produce IFN-γ, as FcRγ- NK cells showed limited potential to differentiate into CD16-/CD25+/CD83+ helper cells. Notwithstanding their deficiencies in responsiveness to innate environmental cues, FcRγ- NK cells responded robustly to adaptive Ab-mediated signaling through CD16. The presence of an expanded population of FcRγ- NK cells with a diminished capacity to respond to IL-18 and to effectively modulate DC function may contribute to disturbances in proper immune homeostasis associated with HIV-1 infection and to defects in the initiation of optimal adaptive antiviral responses.

Mapping the interplay between NK cells and HIV: therapeutic implications.

Although highly effective at durably suppressing plasma HIV-1 viremia, combination antiretroviral therapy (ART) treatment regimens do not eradicate the virus, which persists in long-lived CD4+ T cells. This latent viral reservoir serves as a source of plasma viral rebound following treatment interruption, thus requiring lifelong adherence to ART. Additionally, challenges remain related not only to access to therapy but also to a higher prevalence of comorbidities with an inflammatory etiology in treated HIV-1+ individuals, underscoring the need to explore therapeutic alternatives that achieve sustained virologic remission in the absence of ART. Natural killer (NK) cells are uniquely positioned to positively impact antiviral immunity, in part due to the pleiotropic nature of their effector functions, including the acquisition of memory-like features, and, therefore, hold great promise for transforming HIV-1 therapeutic modalities. In addition to defining the ability of NK cells to contribute to HIV-1 control, this review provides a basic immunologic understanding of the impact of HIV-1 infection and ART on the phenotypic and functional character of NK cells. We further delineate the qualities of "memory" NK cell populations, as well as the impact of HCMV on their induction and subsequent expansion in HIV-1 infection. We conclude by highlighting promising avenues for optimizing NK cell responses to improve HIV-1 control and effect a functional cure, including blockade of inhibitory NK receptors, TLR agonists to promote latency reversal and NK cell activation, CAR NK cells, BiKEs/TriKEs, and the role of HIV-1-specific bNAbs in NK cell-mediated ADCC activity against HIV-1-infected cells.

Identifying inflammatory phenotypes to target mechanism-specific treatments in sepsis.

A clinical trial by Leventogiannis et al.1 suggests that ferritin and HLA-DR monocyte receptor expression can identify septic patients with macrophage-activation-like syndrome (MALS), or immunoparalysis, and that targeting IL-1ra treatment with this strategy may improve outcomes.

Sepsis with liver dysfunction and coagulopathy predicts an inflammatory pattern of macrophage activation.

BACKGROUND: Interleukin-1 receptor antagonists can reduce mortality in septic shock patients with hepatobiliary dysfunction and disseminated intravascular coagulation (HBD + DIC), an organ failure pattern with inflammatory features consistent with macrophage activation. Identification of clinical phenotypes in sepsis may allow for improved care. We aim to describe the occurrence of HBD + DIC in a contemporary cohort of patients with sepsis and determine the association of this phenotype with known macrophage activation syndrome (MAS) biomarkers and mortality. We performed a retrospective nested case-control study in adult septic shock patients with concurrent HBD + DIC and an equal number of age-matched controls, with comparative analyses of all-cause mortality and circulating biomarkers between the groups. Multiple logistic regression explored the effect of HBD + DIC on mortality and the discriminatory power of the measured biomarkers for HBD + DIC and mortality. RESULTS: Six percent of septic shock patients (n = 82/1341) had HBD + DIC, which was an independent risk factor for 90-day mortality (OR = 3.1, 95% CI 1.4-7.5, p = 0.008). Relative to sepsis controls, the HBD + DIC cohort had increased levels of 21 of the 26 biomarkers related to macrophage activation (p < 0.05). This panel was predictive of both HBD + DIC (sensitivity = 82%, specificity = 84%) and mortality (sensitivity = 92%, specificity = 90%). CONCLUSION: The HBD + DIC phenotype identified patients with high mortality and a molecular signature resembling that of MAS. These observations suggest trials of MAS-directed therapies are warranted.

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes.

BACKGROUND: During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV). METHODS: Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome. FINDINGS: MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures. INTERPRETATION: Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection. FUNDING: A full list of the funding sources is detailed in the Acknowledgment section of the manuscript.