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The innate immune system, which senses invading pathogens, plays a critical role as the first line of host defense. After recognition of foreign RNA ligands (e.g., RNA viruses), host cells generate an innate immune or antiviral response via the interferon-mediated signaling pathway. Retinoic acid-inducible gene I (RIG-1) acts as a major sensor that recognizes a broad range of RNA ligands in mammals; however, chickens lack a RIG-1 homolog, meaning that RNA ligands should be recognized by other cellular sensors such as melanoma differentiation-associated protein 5 (MDA5) and toll-like receptors (TLRs). However, it is unclear which of these cellular sensors compensates for the loss of RIG-1 to act as the major sensor for RNA ligands. Here, we show that chicken MDA5 (cMDA5), rather than chicken TLRs (cTLRs), plays a pivotal role in the recognition of RNA ligands, including poly I:C and influenza virus. First, we used a knockdown approach to show that both cMDA5 and cTLR3 play roles in inducing interferon-mediated innate immune responses against RNA ligands in chicken DF-1 cells. Furthermore, targeted knockout of cMDA5 or cTLR3 in chicken DF-1 cells revealed that loss of cMDA5 impaired the innate immune responses against RNA ligands; however, the responses against RNA ligands were retained after loss of cTLR3. In addition, double knockout of cMDA5 and cTLR3 in chicken DF-1 cells abolished the innate immune responses against RNA ligands, suggesting that cMDA5 is the major sensor whereas cTLR3 is a secondary sensor. Taken together, these findings provide an understanding of the functional role of cMDA5 in the recognition of RNA ligands in chicken DF-1 cells and may facilitate the development of an innate immune-deficient cell line or chicken model.

TIGIT expression on natural killer (NK) cells is associated with dysfunction during chronic HIV infection, but the phenotype and biological functions of these cells in the context of acute HIV-1 infection remain poorly understood. Here, 19 acutely infected HIV-1 patients traced at first, third and twelfth month, and age-matched patients with chronic HIV-1 infection were enrolled to investigate the phenotype and functions of TIGIT expression on NK cells. We found that TIGIT-expressing NK cells did not increase in frequency in the first, third and twelfth month of infection until chronic HIV-1 infection lasted over 2 years. The number of TIGIT+NK cells in acute infection was positively associated with HIV-1 viral load (r = 0.53, P = 0.0009). CD96 was significantly upregulated on NK cells after acute infection for 1 month and in chronic infection over 2 years, while CD226 was downregulated in chronic infection over 2 years. Further, at different stages of infection, CD96−CD226+ cells diminished among total NK cells, TIGIT+NK and TIGIT−NK cells, while CD96+CD226− cells expanded. Reduced CD96−CD226+ cells and elevated CD96+CD226− cells among NK cells especially TIGIT−NK cells, had opposite associations with viral load in the first month of infection, as well as CD4 T-cell counts in including the twelfth month and more than 2 years of chronic infection. In both HIV-1-infected individuals and healthy donors, TIGIT was predominantly expressed in NKG2A−NKG2C+NK cells, with a significantly higher proportion than in NKG2A+NKG2C−NK cells. Moreover, the frequencies of TIGIT+NK cells were positively associated with the frequencies of NKG2A−NKG2C+NK cells in acute infection (r = 0.62, P < 0.0001), chronic infection (r = 0.37, P = 0.023) and healthy donors (r = 0.36, P = 0.020). Enhanced early activation and coexpression of CD38 and HLA-DR in TIGIT+NK cells were detected compared to TIGIT−NK cells, both of which were inversely associated with the decrease in CD4 T-cell counts in both acute and chronic HIV-1 infection. The ability of TIGIT+NK cells to produce TNF-α, IFN-γ and CD107a degranulation substance were consistently weaker than that of TIGIT−NK cells in both acute and chronic infection. Moreover, the functionalities of TIGIT+NK cells were lower than those of TIGIT−NK cells, except for TNF-α−CD107a+IFN-γ−NK cells. These findings highlight the phenotype and functional characteristics of TIGIT-expressing NK cells which have poor capabilities in inhibiting HIV-1 replication and maintaining CD4 T-cell counts. [ABSTRACT FROM AUTHOR]

Background: HIV infection results in immune homeostasis perturbations, which is characterized by CD4+ T-cell depletion, immune activation, and inflammation. Effective antiretroviral therapy (ART) does not fully restore immunologic and clinical health in people living with HIV (PLWH). Various drugs have been used to improve their immune status and CD4+ T-cell counts, but no measures have been tested effective. Here we conduct a systematic review and meta-analysis of existing clinical studies on improving CD4+ T-cell count while decreasing inflammation and immune activation. Methods: We retrieved possible relevant publications from a total of five electronic databases and selected eligible studies, which dealt with outcomes of medical therapy for CD4+ T-cell count recovery, inflammation, and immune activation with or without ART. We paid particular attention to immunologic non-responders with a favorable treatment regimen. Results: Thirty-three articles were included in the systematic review and meta-analysis. However, there were no safe and effective medications specific for improving CD4+ T-cell reconstitution. The immunological benefits or adverse events mainly depend on the safety, dosage, and duration of the candidate medication use, as well as whether it is combined with ART. Conclusion: Under the "safe, combined, adequate and long (SCAL)" principles, alternative approaches are needed to accelerate the recovery of CD4+ T-cells, and to prevent adverse long-term outcomes in PLWH with standard ART treatment. [ABSTRACT FROM AUTHOR]

The incidence of syphilis has increased dramatically in men who have sex with men (MSM), especially those with HIV-1 infection. Treponema pallidum and HIV-1 are bidirectionally synergistic, accelerating disease progression reciprocally in co-infected individuals. We have shown that monocytes have different effects on T helper cells at different stages of HIV-1 infection. However, the immunological changes in the three monocyte subsets and in regulatory T cells (Tregs), and the associations between these cell types during syphilis infection among HIV-1-infected MSM remain unclear. Herein, we used cell staining methods to explore changes in monocyte subsets and Tregs and any associations between these cells. We found that the frequency of classical monocytes was higher in the rapid plasma reagin (RPR+) group than in the healthy controls (HCs) and the chronic HIV-1 infection (CHI) plus RPR+ (CHI&RPR+) group. The frequencies of Foxp3+CD25+CD45RA+ and Foxp3+Helios+CD45RA+ Tregs were significantly higher in the RPR+, CHI, and CHI&RPR+ groups than in HCs, whereas the frequency of CD45RA+ Tregs was lower in the CHI&RPR+ group than in CHI group. The frequencies of Foxp3+CD25+CD45RO+ and Foxp3+Helios+CD45RO+ Tregs were lower in the RPR+, CHI, and CHI&RPR+ groups than in HCs. The frequency of intermediate monocytes was inversely correlated with the frequency of CD45RA+ Tregs and positively correlated with the frequency of CD45RO+ Tregs. These results demonstrate for the first time that intermediate monocytes control the differentiation of Treg subsets in Treponema pallidum /HIV-1 co-infections. These findings provide new insights into an immunological mechanism involving monocytes/Tregs in HIV-infected individuals with syphilis. [ABSTRACT FROM AUTHOR]

TIGIT expression on natural killer (NK) cells is associated with dysfunction during chronic HIV infection, but the phenotype and biological functions of these cells in the context of acute HIV-1 infection remain poorly understood. Here, 19 acutely infected HIV-1 patients traced at first, third and twelfth month, and age-matched patients with chronic HIV-1 infection were enrolled to investigate the phenotype and functions of TIGIT expression on NK cells. We found that TIGIT-expressing NK cells did not increase in frequency in the first, third and twelfth month of infection until chronic HIV-1 infection lasted over 2 years. The number of TIGIT + NK cells in acute infection was positively associated with HIV-1 viral load ( r = 0.53, P = 0.0009). CD96 was significantly upregulated on NK cells after acute infection for 1 month and in chronic infection over 2 years, while CD226 was downregulated in chronic infection over 2 years. Further, at different stages of infection, CD96 - CD226 + cells diminished among total NK cells, TIGIT + NK and TIGIT - NK cells, while CD96 + CD226 - cells expanded. Reduced CD96 - CD226 + cells and elevated CD96 + CD226 - cells among NK cells especially TIGIT - NK cells, had opposite associations with viral load in the first month of infection, as well as CD4 T-cell counts in including the twelfth month and more than 2 years of chronic infection. In both HIV-1-infected individuals and healthy donors, TIGIT was predominantly expressed in NKG2A - NKG2C + NK cells, with a significantly higher proportion than in NKG2A + NKG2C - NK cells. Moreover, the frequencies of TIGIT + NK cells were positively associated with the frequencies of NKG2A - NKG2C + NK cells in acute infection ( r = 0.62, P < 0.0001), chronic infection ( r = 0.37, P = 0.023) and healthy donors ( r = 0.36, P = 0.020). Enhanced early activation and coexpression of CD38 and HLA-DR in TIGIT + NK cells were detected compared to TIGIT - NK cells, both of which were inversely associated with the decrease in CD4 T-cell counts in both acute and chronic HIV-1 infection. The ability of TIGIT + NK cells to produce TNF-α, IFN-γ and CD107a degranulation substance were consistently weaker than that of TIGIT - NK cells in both acute and chronic infection. Moreover, the functionalities of TIGIT + NK cells were lower than those of TIGIT - NK cells, except for TNF-α - CD107a + IFN-γ - NK cells. These findings highlight the phenotype and functional characteristics of TIGIT-expressing NK cells which have poor capabilities in inhibiting HIV-1 replication and maintaining CD4 T-cell counts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Lu, Cheung, Zhang, Liu, Li, Yuan, Wang, Liu, Tang, Xia, Wu, Zhang and Su.)

Background: HIV infection results in immune homeostasis perturbations, which is characterized by CD4 + T-cell depletion, immune activation, and inflammation. Effective antiretroviral therapy (ART) does not fully restore immunologic and clinical health in people living with HIV (PLWH). Various drugs have been used to improve their immune status and CD4 + T-cell counts, but no measures have been tested effective. Here we conduct a systematic review and meta-analysis of existing clinical studies on improving CD4 + T-cell count while decreasing inflammation and immune activation. Methods: We retrieved possible relevant publications from a total of five electronic databases and selected eligible studies, which dealt with outcomes of medical therapy for CD4 + T-cell count recovery, inflammation, and immune activation with or without ART. We paid particular attention to immunologic non-responders with a favorable treatment regimen. Results: Thirty-three articles were included in the systematic review and meta-analysis. However, there were no safe and effective medications specific for improving CD4 + T-cell reconstitution. The immunological benefits or adverse events mainly depend on the safety, dosage, and duration of the candidate medication use, as well as whether it is combined with ART. Conclusion: Under the "safe, combined, adequate and long (SCAL)" principles, alternative approaches are needed to accelerate the recovery of CD4 + T-cells, and to prevent adverse long-term outcomes in PLWH with standard ART treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Jiang, Li, Li, Hou, Gao, Huang, Su, Wu, Zhang and Jiang.)

The incidence of syphilis has increased dramatically in men who have sex with men (MSM), especially those with HIV-1 infection. Treponema pallidum and HIV-1 are bidirectionally synergistic, accelerating disease progression reciprocally in co-infected individuals. We have shown that monocytes have different effects on T helper cells at different stages of HIV-1 infection. However, the immunological changes in the three monocyte subsets and in regulatory T cells (Tregs), and the associations between these cell types during syphilis infection among HIV-1-infected MSM remain unclear. Herein, we used cell staining methods to explore changes in monocyte subsets and Tregs and any associations between these cells. We found that the frequency of classical monocytes was higher in the rapid plasma reagin (RPR + ) group than in the healthy controls (HCs) and the chronic HIV-1 infection (CHI) plus RPR + (CHI&RPR + ) group. The frequencies of Foxp3 + CD25 + CD45RA + and Foxp3 + Helios + CD45RA + Tregs were significantly higher in the RPR + , CHI, and CHI&RPR + groups than in HCs, whereas the frequency of CD45RA + Tregs was lower in the CHI&RPR + group than in CHI group. The frequencies of Foxp3 + CD25 + CD45RO + and Foxp3 + Helios + CD45RO + Tregs were lower in the RPR + , CHI, and CHI&RPR + groups than in HCs. The frequency of intermediate monocytes was inversely correlated with the frequency of CD45RA + Tregs and positively correlated with the frequency of CD45RO + Tregs. These results demonstrate for the first time that intermediate monocytes control the differentiation of Treg subsets in Treponema pallidum /HIV-1 co-infections. These findings provide new insights into an immunological mechanism involving monocytes/Tregs in HIV-infected individuals with syphilis.

Persistent immune activation is a striking consequence of HIV-1 infection and a driving force of CD4 + T cell depletion and AIDS events during chronic infection. High level of T cell immune activation associates with antiretroviral therapy (ART)-treated clinical outcomes in chronically HIV-1-infected patients. However, the role of T cell activation during acute infection stage in subsequent CD4 + T cell decline in the absence of ART treatment is unknown. In this study, we enrolled 26 acutely HIV-1-infected patients in the absence of ART treatment from a prospective acute HIV-1 infection cohort in Beijing (PRIMO). A comprehensive analysis of CD4 + and CD8 + T cell immune activation during acute infection stage and the clinical outcomes was studied. We found that patients with higher level of CD4 + T cell activation (%CD38 + HLA-DR + CD4 + T cells) exhibited more effective function (%IL-2 production and %ki67 expression) in CD4 + T cells compared to those from patients without increased T cell activation at the acute phase. Direct correlations were observed between CD4 + T cell activation and the percentages of IL-2-producing or ki67-expressing CD4 + T cells in patients at the acute phase of infection. Importantly, the increased levels of CD4 + T cell immune activation, IL-2 production, and cycling expression during acute infection were associated with less decline of CD4 + T cell after 2 years of infection. However, immune exhaustion molecules in acute infection, including CD160, T cell immunoglobulin and ITIM domain, programmed cell death protein 1, and T cell immunoglobulin and mucin 3, were not associated with the CD4 + T cell depletion. These significant associations of CD4 + T cell activation were not demonstrable for CD8 + T cell activation at the acute phase. Taken together, our observations provide new insight into the possible role of T cell activation in preventing CD4 + T cell depletion during acute HIV-1 infection.

Failure of immune reconstitution increases the risk of AIDS or non-AIDS related morbidity and mortality in HIV-1-infected patients. CD3 + CD4 - CD8 - T cells, which are usually described as double-negative (DN) T cells, display CD4-like helper and immunoregulatory functions. Here, we have measured the percentage of DN T cells in the immune reconstituted vs. non-immune reconstituted HIV-1-infected individuals. We observed that immunological non-responders (INRs) had a low number of DN T cells after long-term antiretroviral therapy (ART), and the number of these cells positively correlated with the CD4 + T cell count. The ART did not result in complete suppression of immune activation recorded by the percentage of CD38 + HLA-DR + CD8 + T cells in INRs, and a strong inverse correlation was observed between DN T cells and immune activation. A low proportion of TGF-β1 + DN T cells was found in INRs. Further mechanism study demonstrated that the level of TGF-β1-producing DN T cells and immune activation had a negative correlation after ART. Taken together, our study suggests that DN T cells control the immunological response in HIV-1-infected patients. These findings expand our understanding of the mechanism of immune reconstitution and could develop specific treatments to return the immune system to homeostasis following initiation of HIV-1 therapy.