The Role of Innate Immunity in Natural Elite Controllers of HIV-1 Infection

Abstract

The natural process of human immunodeficiency virus type 1(HIV-1) infection is characterized by high viral load, immune cell exhaustion, and immunodeficiency, which eventually leads to the stage of acquired immunodeficiency syndrome (AIDS) and opportunistic infections. Rapidly progressing HIV-1 individuals often die of AIDS several years after infection without treatment. The promotion of ART greatly prolongs the survival time of HIV-infected persons. However, some patients have incomplete immune function reconstruction after ART due to latent storage of HIV-infected cells. Therefore, how to achieve a functional cure has always been the focus and hot spot of global AIDS research. Fortunately, the emergence of ECs/LTNPs who can control virus replication naturally has ignited new hope for realizing a functional cure for AIDS. Recently, a special category of infected individuals has attracted attention that can delay the progression of the disease more rigorously than the natural progression of HIV-1 infection described above. These patients are characterized by years of HIV-1 infection, long-term asymptomatic status, and normal CD4+T cell count without ART, classified as HIV-infected long-term nonprogressors (LTNPs) and elite controllers (ECs). Numerous studies have shown that the host and virus jointly determine the progression of HIV-1 infection, in which the level of innate immunity activation plays an important role. As the first line of defense against pathogen invasion, innate immunity is also a bridge to induce adaptive immunity. Compared with natural progressors, innate immunity plays an antiviral role in HIV-1 infection by inducing or activating many innate immune-related factors in the natural ECs. Learning the regulation of ECs immunity, especially the innate immunity in different characteristics, and thus studying the mechanism of the control of disease progression naturally, will contribute to the realization of the functional cure of AIDS. Therefore, this review will explore the relationship between innate immunity and disease progression in ECs of HIV-1 infection from the aspects of innate immune cells, signaling pathways, cytokines, which is helpful to provide new targets and theoretical references for the functional cure, prevention and control of AIDS, and development of a vaccine.

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

“…On the other hand, pDC are very effective secreting high levels of type I IFNs and are critical to induce immune responses to viral infections [11,19]. Reduced frequencies of pDC present in blood also correlates with HIV-1 disease progression and in in PLWH on antiretroviral treatment, and are also enriched in EC [11,19,26]. Furthermore, a specific pDC subpopulation co-expressing high levels of LILRA4 and LILRB4 negatively correlating with blood viral load was enriched in EC compared to progressor individuals with primary HIV-1 infection, in agreement with previous in vitro experiments that showed that pDC from EC displayed higher abilities to inhibit HIV-1 production by infected cells [19,27].…”

“…On the other hand, pDC are very effective secreting high levels of type I IFNs and are critical to induce immune responses to viral infections [11,19]. Reduced frequencies of pDC present in…”

“…cDC comprise CD1c þ and CD141 þ subsets, which display different abilities to stimulate CD4 þ and CD8 þ T cells, respectively. A reduction of cDC frequencies present in blood correlate with HIV-1 disease progression, however, frequencies are preserved in EC even in comparison to people living with HIV-1 (PLWH) on antiretroviral treatment [11,19]. 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].…”

“…Innate immune cells comprise a heterogeneous group of cell subsets, such as myeloid cells and natural killer (NK) cells, that are critical to induce antiviral responses [8,9]. RIG-I-like receptors (RLR), C type lectin receptors (CLR), intracellular DNA and RNA sensors and inflammasome components that are capable of recognizing conserved pathogen-associated molecular patterns (PAMPs) [10,11]. Recognition of PAMPs by these PRRs activates a complex network of signaling pathways leading to the production of pro-inflammatory cytokines and type I and III interferons (IFNs), finally stimulation of other innate cells and modulating the adaptive immune response [12].…”

Mechanism of Viral Suppression among HIV Elite Controllers and Long-Term Nonprogressors in Nigeria and South Africa

“…The mechanism of the host's innate immunity toward achieving a nonprogressive phenotype, as exhibited by HIV controllers, involves, among others, the recruitment of an elevated number of correlating dendritic cells, macrophages, natural killer T cells, monocytes, or natural killer cells [24,32,35]. The high frequency of these innate immune cells is achieved and maintained by an interdependence signaling among the cells and through the action of cytokines, such as IL-12, IL-15, IFN-α, and IFN-β, which partially or together play inhibitory roles in viral replication [31,32,[35][36][37][38][39]. Furthermore, the abundant expression of certain viral restriction factors, which in connection with the immune system disrupts one or more stages of the HIV life cycle, has also been identified as one of the underlying mechanisms of viral suppression among ECs and LTNPs [8,40].…”