Natural killer (NK) cells are important for maintenance of innate immune system stability and serve as a first line of defense against tumors and virus infections; they can act either directly or indirectly and are regulated via co-operation between inhibitory and stimulatory surface receptors. The recently reported inhibitory receptor, TIGIT, can be expressed on the NK cell surface; however, the expression level and function of TIGIT on NK cells during HIV infection is unknown. In this study, for the first time, we investigated the expression and function of TIGIT in NK cells from HIV-infected individuals. Our data demonstrate that the level of TIGIT is higher on NK cells from patients infected with human immunodeficiency virus (HIV) compared with HIV-negative healthy controls. TIGIT expression is inversely correlated with CD4+ T cell counts and positively correlated with plasma viral loads. Additionally, levels of the TIGIT ligand, CD155, were higher on CD4+ T cells from HIV-infected individuals compared with those from healthy controls; however, there was no difference in the level of the activating receptor, CD226, which recognizes the same ligands as TIGIT. Furthermore, TIGIT was found to specifically up-regulated on CD226+ NK cells in HIV-infected individuals, and either rIL-10, or rIL-12 + rIL-15, could induce TIGIT expression on these cells. In addition, high TIGIT expression inhibited the production of interferon-gamma (IFN-γ) by NK cells, while TIGIT inhibition restored IFN-γ production. Overall, these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV.
BackgroundNatural killer (NK) cells have emerged as pivotal players in innate immunity, especially in the defense against viral infections and tumors. Killer immunoglobulin-like receptors (KIRs) – an important recognition receptor expressed on the surface of NK cells – regulate the inhibition and/or activation of NK cells after interacting with human leukocyte antigen (HLA) class I ligands. Various KIR genes might impact the prognosis of many different diseases. The implications of KIR-HLA interaction in HIV disease progression remains poorly understood.MethodsHere, we studied KIR genotypes, mRNA levels, HLA genotypes, CD4+ T cell counts and viral loads in our cohort of Human Immunodeficiency Virus (HIV)-infected individuals, a group that includes HIV long-term nonprogressors (LTNPs) and typical progressors (TPs).ResultsWe found that the frequency of KIR3DS1/L1 heterozygotes with HLA-Bw4-80I gene was much higher in LTNPs than in TPs (P = 0.001) and that the KIR3DL1 homozygotes without HLA-Bw4-80I gene had higher viral loads and lower CD4+ T cell counts (P = 0.014 and P = 0.021, respectively). Our study also confirmed that homozygosity for the HLA-Bw6 allele was associated with rapid disease progression. In addition to the aforementioned results on the DNA level, we observed that higher level expression of KIR3DS1 mRNA was in LTNP group, and that higher level expression of KIR3DL1 mRNA was in TP group.ConclusionsOur data suggest that different KIR-HLA genotypes and different levels of transcripts associate with HIV disease progression.
Natural killer (NK) cells are the first line of defense against pathogens of the immune system and also play an important role in resistance against HIV. The activating receptor NKG2C and the inhibitory receptor NKG2A co-modulate the function of NK cells by recognizing the same ligand, HLA-E. However, the role of NKG2A and NKG2C on viral set point and the prediction of HIV disease progression have been rarely reported. In this study, we determined the expression of NKG2C or NKG2A on the surface of NK cells from 22 individuals with primary HIV infection (PHI) stage and 23 HIV-negative normal control (NC) subjects. The CD4+ T cell count and plasma level of HIV RNA in the infected individuals were longitudinally followed-up for about 720 days. The proportion of NKG2C+NKG2A− NK cells was higher in subjects from the low set point group and was negatively correlated with the viral load. In addition, strong anti-HIV activities were observed in NKG2C+ NK cells from the HIV-positive donors. Furthermore, a proportion of NKG2C+NKG2A− NK cells >35.45%, and a ratio of NKG2C/NKG2A >1.7 were predictive for higher CD4+ T cell counts 720 days after infection. Collectively, the experimental results allow us to draw the conclusion that NKG2C+ NK cells might exert an antiviral effect and that the proportion of NKG2C+NKG2A− NK cells, and the ratio of NKG2C/NKG2A, are potential biomarkers for predicting HIV disease progression.
BackgroundThe events in early HIV infection (EHI) are important determinants of disease severity and progression rate to AIDS, but the mechanisms of pathogenesis in EHI have not been fully understood. Circular RNAs (circRNAs) have been verified as “microRNA sponges” that regulate gene expression through competing endogenous RNA (ceRNA) networks, but circRNA expression profiles and their contribution to EHI pathogenesis are still unclear.MethodsTwo different libraries were constructed with RNA from human peripheral blood mononuclear cells from 3 HARRT-naive EHI patients and 3 healthy controls (HCs). The complete transcriptomes were sequenced with RNA sequencing (RNA-Seq) and miRNA sequencing (miRNA-Seq). The differentially expressed (DE) RNAs were validated with RT-qPCR. The circRNA profile and circRNA-associated-ceRNA network in EHI were analyzed with the integrated data of RNA-Seq and miRNA-Seq. Gene ontology (GO) analysis was used to annotate the circRNAs involved in the circRNA-associated-ceRNA networks.ResultsA total of 1365 circRNAs, 30 miRNAs, and 2049 mRNAs were differentially expressed between HARRT-naive EHI patients and HCs. A ceRNA network was constructed with 516 DE circRNAs and 903 DE mRNAs that shared miR response elements with 21 DE miRNAs. GO analysis demonstrated the multiple roles of the circRNAs enriched in EHI with circRNA-associated-ceRNA networks, such as immune response, inflammatory response and defense responses to virus, 67 circRNAs were revealed to be potentially involved in HIV-1 replication through regulating the expression of CCNK, CDKN1A and IL-15.ConclusionsThis study, for the first time, revealed a large circRNA profile and complex pathogenesis roles of circRNAs in EHI. A group of enriched circRNAs and associated circRNA-associated-ceRNA networks might contribute to HIV replication regulation and provide novel potential targets for both the pathogenesis of EHI and antiviral therapy.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1706-1) contains supplementary material, which is available to authorized users.
We found a significant increase in G-MDSCs in PHI patients that was related to disease progression and PD-L1 was used by MDSCs to inhibit CD8 T cells in HIV infection. Our data improve the understanding of HIV pathogenesis in PHI.
The ATP synthase (F-ATPase) is a highly complex rotary machine that synthesizes ATP, powered by a proton electrochemical gradient. Why did evolution select such an elaborate mechanism over arguably simpler alternating-access processes that can be reversed to perform ATP synthesis? We studied a systematic enumeration of alternative mechanisms, using numerical and theoretical means. When the alternative models are optimized subject to fundamental thermodynamic constraints, they fail to match the kinetic ability of the rotary mechanism over a wide range of conditions, particularly under low-energy conditions. We used a physically interpretable, closed-form solution for the steady-state rate for an arbitrary chemical cycle, which clarifies kinetic effects of complex free-energy landscapes. Our analysis also yields insights into the debated "kinetic equivalence" of ATP synthesis driven by transmembrane pH and potential difference. Overall, our study suggests that the complexity of the F-ATPase may have resulted from positive selection for its kinetic advantage.ATP synthase | kinetic mechanism | free-energy landscape | nonequilibrium steady state | evolution T he F-ATPase performs molecular-level free-energy (FE) transduction to phosphorylate ADP and yield ATP, the primary energy carrier that drives a vast range of cellular processes. It spurred Mitchell's chemiosmotic hypothesis (1) and Boyer's now-validated proposal for the binding-change mechanism (2) in which a proton electrochemical gradient is transduced to rotationbased mechanical energy and then back to chemical FE as ADP is phosphorylated. The F-ATPase's two-domain uniaxial rotary structure is conserved across all three domains of life (3-6), and details of its function have been the subject of a multitude of studies (e.g., refs. 7-30).Here, we address a relatively narrow question with potentially significant evolutionary implications: Why is ATP synthesized by a rotary mechanism instead of a potentially much simpler alternating-access mechanism (Fig. 1)? Using thermodynamic and kinetic constraints, we address the question of whether evolution tends to arrive at optimal molecular processes (31), building on established concepts of optimality-derived evolutionary convergence (32, 33). Presumably, performance advantages in the central task of ATP synthesis would be under significant evolutionary pressure. Previous modeling studies of the F-ATPase have addressed structural and mechanistic questions about the rotary mechanism (e.g., refs. 11-20), but not the metaissue of the mechanism itself compared with alternatives.To assess whether the rotary mechanism possesses any intrinsic performance advantage, we constructed a series of kinetic models abstracted from known mechanisms (Fig. 1). Beyond the rotarybased model, we considered a series of alternating-access analogs (Fig. 2), building on the demonstrated capacity for ATP-hydrolyzing transporters to be driven in reverse to synthesize ATP (34, 35). The discrete-state models do not include structural details, bu...
BACKGROUND:A substantial percentage (10%-15%) of HIV-infected individuals experience a sharp decline in CD4 ϩ T-cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) vs chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy.
In the past 37 years, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has undergone various major transmission routes in China, with the world most complex co-circulating HIV-1 subtypes, even the prevalence is still low. In response to the first epidemic outbreak of HIV in injecting drug users and the second one by illegal commercial blood collection, China issued the Anti-Drug Law and launched the Blood Donation Act and nationwide nucleic acid testing, which has avoided 98,232 to 211,200 estimated infections and almost ended the blood product-related infection. China has been providing free antiretroviral therapy (ART) since 2003, which covered >80% of the identified patients and achieved a viral suppression rate of 91%. To bend the curve of increasing the disease burden of HIV and finally end the epidemic, China should consider constraining HIV spread through sexual transmission, narrowing the gaps in identifying HIV cases, and the long-term effectiveness and safety of ART in the future.
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