Monkeying Around: Using Non-human Primate Models to Study NK Cell Biology in HIV Infections

Abstract

Natural killer (NK) cells are the major innate effectors primed to eliminate virus-infected and tumor or neoplastic cells. Recent studies also suggest nuances in phenotypic and functional characteristics among NK cell subsets may further permit execution of regulatory and adaptive roles. Animal models, particularly non-human primate (NHP) models, are critical for characterizing NK cell biology in disease and under homeostatic conditions. In HIV infection, NK cells mediate multiple antiviral functions via upregulation of activating receptors, inflammatory cytokine secretion, and antibody dependent cell cytotoxicity through antibody Fc-FcR interaction and others. However, HIV infection can also reciprocally modulate NK cells directly or indirectly, leading to impaired/ineffective NK cell responses. In this review, we will describe multiple aspects of NK cell biology in HIV/SIV infections and their association with viral control and disease progression, and how NHP models were critical in detailing each finding. Further, we will discuss the effect of NK cell depletion in SIV-infected NHP and the characteristics of newly described memory NK cells in NHP models and different mouse strains. Overall, we propose that the role of NK cells in controlling viral infections remains incompletely understood and that NHP models are indispensable in order to efficiently address these deficits.

V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers

“…Dissecting polyclonal immune responses and viral epitope signatures in natural infection and vaccinees reveals “humoral footprints” that aid vaccine design [19,20,111,218,219,220]. Since human vaccine trials require extensive logistics and financial efforts, animal models are widely used [10,11,12]. However, in comparison to humans, animal models exhibit incongruences in host and viral genomes, immune repertoires, and overall responsiveness.…”

“…Aside from the few human vaccine efficacy trials [9], the majority of HIV vaccine research has been done using NHPs as the best available animal model of HIV/AIDS [10,11,12,13]. NHPs exhibit a high genetic and immunologic homology with humans; e.g., the human and rhesus macaque genomes are ~91% identical (93.5% in the alignable sequence without small indels), and humans and chimpanzees even share ~98.5% of their genomes [14].…”

Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques

“…The Ly49 family of receptors in the mouse has been shown to have some analogous functions to human KIRs; however in terms of their structure, these molecules are highly dissimilar (12). In contrast to murine models, non-human primates, specifically rhesus macaques (RMs), are phylogenetically closely related to humans, and their NK cells share many phenotypic and functional properties with human NK cells (13–15).…”

Delineation and Modulation of the Natural Killer Cell Transcriptome in Rhesus Macaques During ZIKV and SIV Infections

“…Though they play a substantial role in the regulation of viral infections and nascent neoplasms, these immune cells remain poorly investigated compared to their adaptive counterparts, T cells and B cells. Although NK cells are considered a heterogenous population, they can be broadly classified as cytokine-producing or cytotoxic cells (Manickam et al, 2019). Their functional and phenotypic characterization may also vary depending on tissue localization or disease state allowing NK cells to be versatile in their responses.…”

“…Their functional and phenotypic characterization may also vary depending on tissue localization or disease state allowing NK cells to be versatile in their responses. In many non-human primates (NHP), NK cells are defined as being CD14 − CD20 − CD3 − CD159A/C + and in rhesus macaques the predominant population in blood can be additionally defined by the expression of CD16, whereas in certain tissues CD56 is generally upregulated on the cell surface of NK cells (Reeves et al, 2010;Manickam et al, 2019).…”