Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

Abstract

Although antiretroviral therapy (ART) has drastically changed the lives of people living with human immunodeficiency virus-1 (HIV-1), long-term treatment has been associated with a vast array of comorbidities. Therefore, a cure for HIV-1 remains the best option to globally eradicate HIV-1/acquired immunodeficiency syndrome (AIDS). However, development of strategies to achieve complete eradication of HIV-1 has been extremely challenging. Thus, the control of HIV-1 replication by the host immune system, namely functional cure, has long been studied as an alternative approach for HIV-1 cure. HIV-1 elite controllers (ECs) are rare individuals who naturally maintain undetectable HIV-1 replication levels in the absence of ART and whose immune repertoire might be a desirable blueprint for a functional cure. While the role(s) played by distinct human leukocyte antigen (HLA) expression and CD8+ T cell responses expressing cognate ligands in controlling HIV-1 has been widely characterized in ECs, the innate immune phenotype has been decidedly understudied. Comparably, in animal models such as HIV-1-infected humanized mice and simian Immunodeficiency Virus (SIV)-infected non-human primates (NHP), viremic control is known to be associated with specific major histocompatibility complex (MHC) alleles and CD8+ T cell activity, but the innate immune response remains incompletely characterized. Notably, recent work demonstrating the existence of trained innate immunity may provide new complementary approaches to achieve an HIV-1 cure. Herein, we review the known characteristics of innate immune responses in ECs and available animal models, identify gaps of knowledge regarding responses by adaptive or trained innate immune cells, and speculate on potential strategies to induce EC-like responses in HIV-1 non-controllers.

Effective innate immune response in natural HIV-1 controllers. Can mimicking lead to novel preventive and cure strategies against HIV-1?

“…On the contrary, higher expression NKp46 activating receptor has been reported in circulating NK cells from EC [21]. Finally, interaction between protective HLA-B∗57 and KIR3DL1 and KIR3DS1 in EC can suppress viral replication [21,41 ▪ ]. HLA-B∗57 has also been reported to play a role in viral control by CD8 + T cells, and although no evidence of synergy has yet been found, it highlights the importance of NK cells responses on EC to maintain viral control.…”

“…Interestingly, circulating cDC from EC display higher capacities of antigen presentation associated with higher expression of activating immunomodulatory receptors such as Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB1) and LILRB3 [20]. Previous studies reported that improved detection of HIV-1 transcripts by the Cyclic GMP-AMP Synthase pathway in cDC which might contribute to activation of CD8 þ T cells in HIV-1 controllers [5,21]. Subsequent transcriptional studies at the single-cell level identified an activation state of circulating cDC from EC characterized by high interferon gene expression signatures regulated by TANK-Binding Kinase 1, co-expression of high levels of CD64 and Programmed Death-Ligand 1 (PD-L1) and superior functional capacities to activate polyfunctional HIV-1-specific CD8þ T cell responses [6].…”

“…In fact, lack of expression of NKG2C, a marker associated with memory NK, has been associated with lower HIV-1 viral load set point [33]. In addition, recent studies in rhesus macaques described the existence of adaptive NK cells against the Simian Immunodeficiency Virus (SIV), pointing to the possibility to generate HIV-specific trained NK cells as a therapy [21,34]. Therefore, the role of adaptive memory-like NK cells in natural control of HIV-1 remains unclear.…”

“…Previous tested immunotherapies against HIV-1 did not efficiently prevent viral rebound after treatment interruption [43,44], pointing to the need to module and fine-tune innate immune cells contributing to antiviral responses such as DCs and NK cells to mimic antiviral immunity in controllers [15,21,45,46]. Due to the important contribution of innate responses in natural viral control in EC, recent strategies have tried to mimic the enhanced antiviral function of DC and NK cell states in preventive and therapeutic purposes by either inducing an EC-like trained immunity state or by other alternative strategies [47].…”

“…In addition, two different studies identified higher expression of NKG2D on circulating NK cells from EC, compared to PLWH, and less downregulation of NKG2D ligands by HIV-1 Nef, which leads to increased susceptibility of CD4 + infected cells to ADCC [39,40 ▪ ]. On the contrary, higher expression NKp46 activating receptor has been reported in circulating NK cells from EC [21]. Finally, interaction between protective HLA-B∗57 and KIR3DL1 and KIR3DS1 in EC can suppress viral replication [21,41 ▪ ].…”