Reduced Immunosenescence of Peripheral Blood T Cells in Parkinson's Disease with CMV Infection Background.

Immunosenescence is a process of remodeling the immune system under the influence of chronic inflammation during aging. Parkinson's disease (PD) is a common age-associated neurodegenerative disorder and is frequently accompanied by neuroinflammation. On the other hand, cytomegalovirus (CMV), one of the most spread infections in humans, may induce chronic inflammation which contributes to immunosenescence, differentiation and the inflation of T cells and NK cells. Currently, there is no clear understanding of immunosenescence severity in PD patients infected with CMV. In this study, we analyzed differentiation stages and immunosenescence characteristics of T cells and NK cells in 31 patients with mild and moderate PD severity, 33 age-matched and 30 young healthy donors. The PD patients were 100% CMV-seropositive compared to 76% age-matched and 73% young CMV-infected healthy donors. The proportion of effector memory T cells re-expressing CD45RA, CD57+CD56- T cells and CD57+CD56+ T cells was significantly reduced in PD patients compared with CMV-seropositive age-matched healthy individuals. The CD57+CD56- T cell proportion in PD patients was similar to that of CMV-seropositive young healthy donors. Thus, PD is characterized by reduced peripheral blood T cell immunosenescence, even against the background of CMV infection.

Lymphocyte subsets as a predictor of severity and prognosis in COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) had become a worldwide health threat. Early prediction of the severity of COVID-19 patients was important for reducing death rate and controlling this disease. METHODS AND MATERIALS: A total of 301 patients confirmed with COVID-19 in Wuhan from 8 February to 10 April 2020 were included. Clinical data were collected and analyzed. Diagnostic and prognostic utility of blood cell counts and lymphocyte subsets in COVID-19 patients were investigated. The receiver operator characteristic curve (ROC) was used in discriminating the mild and severe/critical cases. RESULTS: There were difference in blood cell counts and lymphocyte subsets among mild, severe and critical patients, which were also influenced by comorbidities and duration of disease. The area under the ROC of lymphocyte, CD3+ T cells, CD4+ T cells, and CD8+ T cells were 0.718, 0.721, 0.718, and 0.670, which were higher than that of other hematological parameters. The optimal threshold was 1205, 691, 402, and 177 per µl, respectively. Patients with higher counts of lymphocyte, CD3+ T cells, CD4+ T cells, or CD8+ T cells were correlated with shorter length of stay in hospital (p < 0.05). Multivariable Cox regression analysis showed disease severity, CD3+ T cells counts and time when the nucleic acid turned negative were independent risk factors for in-hospital death of COVID-19 patients (p < 0.05). CONCLUSION: Blood cell counts and lymphocyte subsets correlated with severity of COVID-19.

Alterations in lymphocyte subsets and monocytes in patients diagnosed with SARS-CoV-2 pneumonia: a mini review of the literature.

OBJECTIVE: Complete blood count parameters are frequently altered in COVID-19 patients. Leucopenia and lymphopenia are the most common findings. This is not specific to COVID-19 as similar alterations are found in various other viral infections. This work is intended to summarize the evidence regarding white blood cell and lymphocyte subset alterations in COVID-19 and their clinical implications. MATERIALS AND METHODS: A PubMed search was conducted to identify relevant original studies. Articles not available in English or referring exclusively to pediatric patients were excluded. The study was designed as a narrative review from its inception. RESULTS: Complete white blood cell number and lymphocytes may be reduced in COVID-19 patients. Circulating CD4+ cells (helper T lymphocytes), CD8+ cells (cytotoxic T lymphocytes), regulatory T cells and natural killer (NK) cells may be reduced, with a greater reduction observed in critically ill patients. CD4+ and regulatory cell deficiencies may contribute to the cytokine storm and subsequent tissue damage observed in severe COVID-19 infection. NK and CD8+ cell deficiency might delay infection clearance. These aberrations of cellular immunity may contribute significantly to the pathogenesis of the disease. Alterations observed in monocyte function can also be implicated as they are effector cells responsible for tissue damage and remodeling. B cell dysfunction and maturation abnormalities have also been reported, suggesting that the virus also impairs humoral immunity. CONCLUSIONS: Lymphocyte subset abnormalities may be useful prognostic biomarkers for COVID-19, with circulating CD8+ cell count being the most promising as a predictor of severe disease requiring mechanical ventilation and mortality.

Single-cell epigenomic landscape of peripheral immune cells reveals establishment of trained immunity in individuals convalescing from COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often causes severe complications and even death. However, asymptomatic infection has also been reported, highlighting the difference in immune responses among individuals. Here we performed single-cell chromatin accessibility and T cell-receptor analyses of peripheral blood mononuclear cells collected from individuals convalescing from COVID-19 and healthy donors. Chromatin remodelling was observed in both innate and adaptive immune cells in the individuals convalescing from COVID-19. Compared with healthy donors, recovered individuals contained abundant TBET-enriched CD16+ and IRF1-enriched CD14+ monocytes with sequential trained and activated epigenomic states. The B-cell lineage in recovered individuals exhibited an accelerated developmental programme from immature B cells to antibody-producing plasma cells. Finally, an integrated analysis of single-cell T cell-receptor clonality with the chromatin accessibility landscape revealed the expansion of putative SARS-CoV-2-specific CD8+ T cells with epigenomic profiles that promote the differentiation of effector or memory cells. Overall, our data suggest that immune cells of individuals convalescing from COVID-19 exhibit global remodelling of the chromatin accessibility landscape, indicative of the establishment of immunological memory.

The contributory role of lymphocyte subsets, pathophysiology of lymphopenia and its implication as prognostic and therapeutic opportunity in COVID-19.

The incidence of the novel coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought daunting complications for people as well as physicians around the world. An ever-increasing number of studies investigating the characteristics of the disease, day by day, is shedding light on a new feature of the virus with the hope that eventually these efforts lead to the proper treatment. SARS-CoV-2 activates antiviral immune responses, but in addition may overproduce pro-inflammatory cytokines, causing uncontrolled inflammatory responses in patients with severe COVID-19. This condition may lead to lymphopenia and lymphocyte dysfunction, which in turn, predispose patients to further infections, septic shock, and severe multiple organ dysfunction. Therefore, accurate knowledge in this issue is important to guide clinical management of the disease and the development of new therapeutic strategies in patients with COVID-19. In this review, we provide a piece of valuable information about the alteration of each subtype of lymphocytes and important prognostic factors associated with these cells. Moreover, through discussing the lymphopenia pathophysiology and debating some of the most recent lymphocyte- or lymphopenia-related treatment strategies in COVID-19 patients, we tried to brightening the foreseeable future for COVID-19 patients, especially those with severe disease.

EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count.

OBJECTIVES: The immunologic profile and opportunistic viral DNA increase were monitored in Italian patients with COVID-19 in order to identify markers of disease severity. METHODS: A total of 104 patients infected with SARS-CoV-2 were evaluated in the study. Of them, 42/104 (40.4%) were hospitalized in an intensive care unit (ICU) and 62/104(59.6%) in a sub-intensive care unit (SICU). Human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), Parvovirus B19 and Human Herpesvirus 6 virus reactivations were determined by real-time PCR, and lymphocyte subpopulation counts were determined by flow cytometry. RESULTS: Among opportunistic viruses, only EBV was consistently detected. EBV DNA was observed in 40/42 (95.2%) of the ICU patients and in 51/61 (83.6%) of the SICU patients. Comparing the two groups of patients, the EBV DNA median level among ICU patients was significantly higher than that observed in SICU patients. In parallel, a significant reduction of CD8 T cell and NK count in ICU patients as compared with SICU patients was observed (p<0.05). In contrast, B cell count was significantly increased in ICU patients (p=0.0172). CONCLUSIONS: A correlation between reduced CD8+ T cells and NK counts, EBV DNA levels and COVID-19 severity was observed. Other opportunistic viral infections were not observed. The relationship between EBV load and COVID-19 severity should be further evaluated in longitudinal studies.

CD4 and CD8 Lymphocyte Counts as Surrogate Early Markers for Progression in SARS-CoV-2 Pneumonia: A Prospective Study.

BACKGROUND: COVID-19 pathophysiology and the predictive factors involved are not fully understood, but lymphocytes dysregulation appears to play a role. This paper aims to evaluate lymphocyte subsets in the pathophysiology of COVID-19 and as predictive factors for severe disease. PATIENT AND METHODS: A prospective cohort study of patients with SARS-CoV-2 bilateral pneumonia recruited at hospital admission. Demographics, medical history, and data regarding SARS-CoV-2 infection were recorded. Patients systematically underwent complete laboratory tests, including parameters related to COVID-19 as well as lymphocyte subsets study at the time of admission. Severe disease criteria were established at admission, and patients were classified on remote follow-up according to disease evolution. Linear regression models were used to assess associations with disease evolution, and Receiver Operating Characteristic (ROC) and the corresponding Area Under the Curve (AUC) were used to evaluate predictive values. RESULTS: Patients with critical COVID-19 showed a decrease in CD3+CD4+ T cells count compared to non-critical (278 (485 IQR) vs. 545 (322 IQR)), a decrease in median CD4+/CD8+ ratio (1.7, (1.7 IQR) vs. 3.1 (2.4 IQR)), and a decrease in median CD4+MFI (21,820 (4491 IQR) vs. 26,259 (3256 IQR)), which persisted after adjustment. CD3+CD8+ T cells count had a high correlation with time to hospital discharge (PC = -0.700 (-0.931, -0.066)). ROC curves for predictive value showed lymphocyte subsets achieving the best performances, specifically CD3+CD4+ T cells (AUC = 0.756), CD4+/CD8+ ratio (AUC = 0.767), and CD4+MFI (AUC = 0.848). CONCLUSIONS: A predictive value and treatment considerations for lymphocyte subsets are suggested, especially for CD3CD4+ T cells. Lymphocyte subsets determination at hospital admission is recommended.

Long-term infection of SARS-CoV-2 changed the body's immune status.

The outbreak of SARS-CoV-2-associated pneumonia, a disease called COVID-19, has caused a pandemic worldwide. To investigate the immune responses after infection of SARS-CoV-2 in non-critical patients may help to better understand the disease progression. We collected 334 confirmed COVID-19 cases including 212 still in hospital with nucleic acid test positive on halfway for SARS-CoV-2 and 122 discharged from hospital, compared specific antibodies, immune cells, and cytokine changes between the hospitalized and discharged patients. The hospitalized patients had a longer illness time compared with discharged patients. Analysis of viral loads explained long-term or persistent infection of SARS-CoV-2, which existed with the median time of 18.5 days of the positive nucleic acid test. Serum analysis showed that the specific anti-N IgG antibody was positive in all detected patients after infection of two weeks. Neutrophils, Monocytes, NK cells, and CD4+ T cells significantly increased, while total lymphocytes and CD8+ T cells decreased from non-critical hospitalized patients after longer-term infection. Further analysis of the cytokines showed that IL-6, TNF-α, IFN-γ, IL-2, IL-4, and IL-10 from the hospitalized patients were significantly higher, indicating a potential of the increased CD4+ T cell differentiation.

The underlying changes and predicting role of peripheral blood inflammatory cells in severe COVID-19 patients: A sentinel?

BACKGROUND: The underlying changes of peripheral blood inflammatory cells (PBICs) in COVID-19 patients are little known. Moreover, the risk factors for the underlying changes of PBICs and their predicting role in severe COVID-19 patients remain uncertain. MATERIAL AND METHODS: This retrospective study including two cohorts: the main cohort enrolling 45 patients of severe type serving as study group, and the secondary cohort enrolling 12 patients of no-severe type serving as control group. The PBICs analysis was based on blood routine and lymphocyte subsets. The inflammatory cell levels were compared among patients according to clinical classifications, disease-associated phases, as well as one-month outcomes. RESULTS: Compared with patients of non-severe type, the patients of severe type suffered from significantly decreased counts of lymphocytes, eosinophils, basophils, but increased counts of neutrophils. These PBICs alterations got improved in recovery phase, but persisted or got worse in aggravated phase. Compared with patients in discharged group, the patients in un-discharged/died group suffered from decreased counts of total T lymphocytes, CD4 + T lymphocytes, CD8 + T lymphocytes, as well as NK cells at 2 weeks after treatment. Clinical classification-critically severe was the independently risk factor for lymphopenia (OR = 7.701, 95%CI:1.265-46.893, P = 0.027), eosinopenia (OR = 5.595, 95%CI:1.008-31.054, P = 0.049), and worse one-month outcome (OR = 8.984; 95%CI:1.021-79.061, P = 0.048). CONCLUSION: Lymphopenia and eosinopenia may serve as predictors of disease severity and disease progression in COVID-19 patients, and enhancing the cellular immunity may contribute to COVID-19 treatment. Thus, PBICs might become a sentinel of COVID-19, and it deserves attention during COVID-19 treatment.

Intravenous infusion of human umbilical cord Wharton's jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia.

The novel coronavirus disease 2019 (COVID-19) has grown to be a global public health emergency since patients were first detected in Wuhan, China. Thus far, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. The immune system and inflammation are proposed to play a central role in COVID-19 pathogenesis. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. Intravenous infusion of MSCs has shown promising results in COVID-19 treatment. Here, we report a case of a severe COVID-19 patient treated with human umbilical cord Wharton's jelly-derived MSCs (hWJCs) from a healthy donor in Liaocheng People's Hospital, China, from February 24, 2020. The pulmonary function and symptoms of the patient with COVID-19 pneumonia was significantly improved in 2 days after hWJC transplantation, and recovered and discharged in 7 days after treatment. After treatment, the percentage and counts of lymphocyte subsets (CD3+, CD4+, and CD8+ T cell) were increased, and the level of IL-6, TNF-α, and C-reactive protein is significantly decreased after hWJC treatment. Thus, the intravenous transplantation of hWJCs was safe and effective for the treatment of patients with COVID-19 pneumonia, especially for the patients in a critically severe condition. This report highlights the potential of hWJC infusions as an effective treatment for COVID-19 pneumonia.

Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade.

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.

Co-infection with feline retrovirus is related to changes in immunological parameters of cats with sporotrichosis.

Feline sporotrichosis due to Sporothrix brasiliensis is frequently severe and often correlated to zoonotic transmission. Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) cause immunodeficiency in cats; no association has been identified with critical cases of sporotrichosis. Moreover, the cytokine profile in Sporothrix-infected cats and a potential impact of retrovirus co-infections on their immunity is unknown. This study assessed immunological parameters in cats with sporotrichosis with and without FIV or FeLV co-infection. FeLV infection was detected by antigen ELISA and by provirus PCR. FIV infection was investigated through ELISA and Western blot. Cytokine transcription (IFN-γ, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α) was quantified using RT-qPCR and lymphocyte subpopulations (CD4, CD8, CD5 and CD21) were assessed by flow cytometry. Thirty cats with sporotrichosis were recruited to the study, including three FIV-positive and five FeLV-positive (progressive infection) cats. One cat with regressive FeLV infection was excluded from statistics. In comparison to retrovirus-negative cats, FIV-positive cats and FeLV-positive cats had higher IL-10 levels, FeLV-positive cats had lower IL-4 levels and FIV-positive cats had lower IL-12 levels and a lower CD4+/CD8+ ratio. Remarkably, all cats with poor general condition were FeLV (progressive infection) or FIV-positive, but the retrovirus status was not associated with the sporotrichosis treatment length or outcome. The immunological changes and the more severe clinical presentation observed in cats with retrovirus co-infections encourage future prospective studies that address the impact of these changes on prognostic determinants of feline sporotrichosis and the development of new therapy strategies that control disease spread.

Impact of CMV and EBV on Immune Recovery After Allogeneic Hematopoietic Cell Transplantation in Children.

BACKGROUND/AIM: Immune recovery is a key factor in the management of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study analyzed the factors contributing to immune reconstitution after allo-HSCT. PATIENTS AND METHODS: Overall, 65 children with malignant or non-malignant diseases were included in multivariate analyses. RESULTS: The following factors contributed to a faster immune recovery: peripheral blood as a stem cell source and reactivation of CMV infection for CD3+ and CD4+ lymphocyte subpopulations; reactivation of CMV infection for CD8+ subset; donor EBV-IgG+ and no EBV reactivation for CD19 lymphocytes; recipient age below 10 years and peripheral blood as a stem cell source for NK cells. For CD2 and CD4/CD8 ratio no factor was significant in multivariate analysis. CONCLUSION: Patients receiving a graft from an EBV-IgG-positive donor and not having early EBV post-transplant viremia show faster recovery of the B-cells, while patients with early CMV-DNA-emia have a better re-establishment of T-cell subsets.

CD30 Characterizes Polylobated Lymphocytes and Disease Progression in HTLV-1-Infected Individuals.

Purpose: Although expression of CD30 is reported in a subset of adult T-cell leukemia/lymphoma cases, its clinicopathologic significance is poorly understood. We aimed to characterize CD30-positive cells and clarify their tumorigenic role in human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells.Experimental Design: CD30-positive peripheral blood mononuclear cells from individuals with differing HTLV-1 disease status were characterized, and the role of CD30 signaling was examined using HTLV-1-infected cell lines and primary cells.Results: CD30-positive cells were detected in all samples examined, and the marker was coexpressed with both CD25 and CD4. This cell population expanded in accordance with disease progression. CD30-positive cells showed polylobation, with some possessing "flower cell" features, active cycling, and hyperploidy. CD30 stimulation of HTLV-1-infected cell lines induced these features and abnormal cell division, with polylobation found to be dependent on the activation of PI3K. The results thus link the expression of CD30, which serves as a marker for HTLV-1 disease status, to an active proliferating cell fraction featuring polylobation and chromosomal aberrations. In addition, brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated with auristatin E, was found to reduce the CD30-positive cell fraction.Conclusions: Our results indicate that CD30-positive cells act as a reservoir for tumorigenic transformation and clonal expansion during HTLV-1 infection. The CD30-positive fraction may thus be a potential molecular target for those with differing HTLV-1 disease status. Clin Cancer Res; 24(21); 5445-57. ©2018 AACR.

Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants.

Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization. FLIPS provides a genome-scale perspective that addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% of proviruses as intact and potentially replication competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses, suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.

Near patient CD4 count in a hospitalized HIV patient population.

BACKGROUND: Point-of-care (POC) CD4 T-cell counting is increasingly recognized as providing improved linkage-to-care during management of HIV infection, particularly in resource-limited settings where disease burden is highest. This study evaluated prototype POC CD4 T-cell counters from MBio Diagnostics in the context of low CD4 count, hospitalized patients in Mozambique. This study measured system performance when presented with challenging, low count samples from HIV/AIDS patients with acute illnesses resulting in hospitalization. METHODS: Forty whole blood samples were collected from donors on the medical service at Maputo Central Hospital and absolute CD4 counts were generated on the MBio CD4 system and a reference laboratory using flow cytometry. RESULTS: The mean and median CD4 counts by the flow cytometry reference were 173 and 80 cells/µL, respectively. Correlation between the MBio CD4 System and the reference was good. Bland-Altman analysis showed a mean bias of +15 cells/µL (+9 to +21 cells/µL, 95% CI), and limits of agreement of -47 to 77 cells/µL. For samples with counts >100 cells/µL (N = 14), the mean coefficient of variation was 7.3%. For samples with counts <50 cells/µL, mean absolute bias of replicate samples was 4.8 cells/µL. When two MBio readers were compared, Bland-Altman bias was -4 cells/µL (-13 to +6 cells/µL, 95% CI), and limits of agreement of -63 and +55 cells/µL. CONCLUSIONS: The MBio System holds promise as a POC system for quantitation of CD4 T cells in resource-limited settings given system throughput (80-100 cartridges/day), design simplicity, and ease-of-use. © 2015 International Clinical Cytometry Society.

Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6+ CD4+ T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection.

In this study, we investigated the effect of Toll-like receptor 2 (TLR2) ligation on the permissiveness of activated CD4+ T cells to HIV-1 infection by focusing our experiments on the relative susceptibility of cell subsets based on their expression of CCR6. Purified primary human CD4+ T cells were first subjected to a CD3/CD28 costimulation before treatment with the TLR2 agonist Pam3CSK4. Finally, cells were inoculated with R5-tropic HIV-1 particles that permit us to study the effect of TLR2 triggering on virus production at both population and single-cell levels. We report here that HIV-1 replication is augmented in CD3/CD28-costimulated CCR6+ CD4+ T cells upon engagement of the cell surface TLR2. Additional studies indicate that a higher virus entry and polymerization of the cortical actin are seen in this cell subset following TLR2 stimulation. A TLR2-mediated increase in the level of phosphorylated NF-κB p65 subunit was also detected in CD3/CD28-costimulated CCR6+ CD4+ T cells. We propose that, upon antigenic presentation, an engagement of TLR2 acts specifically on CCR6+ CD4+ T cells by promoting virus entry in an intracellular milieu more favorable for productive HIV-1 infection. IMPORTANCE: Following primary infection, HIV-1 induces an immunological and structural disruption of the gut mucosa, leading to bacterial translocation and release of microbial components in the bloodstream. These pathogen-derived constituents include several agonists of Toll-like receptors that may affect gut-homing CD4+ T cells, such as those expressing the chemokine receptor CCR6, which are highly permissive to HIV-1 infection. We demonstrate that TLR2 ligation in CD3/CD28-costimulated CCR6+ CD4+ T cells leads to enhanced virus production. Our results highlight the potential impact of bacterial translocation on the overall permissiveness of CCR6+ CD4+ T cells to productive HIV-1 infection.

HIV and host immunogenetics: unraveling the role of HLA-C.

Host genetic factors play a major role in determining the outcome of many infections including human immunodeficiency virus (HIV). Multiple host factors have been studied till date showing their varied role in susceptibility or resistance to HIV infection. HLA-C, however, has been recently started gaining interest in researchers mind revealing its polymorphisms to have an important effect on viral load set-points, disease progression as well as transmission. In this review report, we have compiled these significant findings of HLA-C in HIV infection, in an attempt to highlight the need for further research in the area in different ethnic population to establish its role in the infection.

HIV infection: focus on the innate immune cells.

Innate immune cells play a critical role during the onset of HIV infection and remain active until the final events that characterize AIDS. The viral impact on innate immune cell response may be a result of direct infection or indirect modulation, and each cell type responds in a specific manner to HIV. During HIV infection, the immune system works in a dynamic way, where innate and adaptive cells contribute with each other stimulating their function and modulating phenotypes and consequently infection resolution. Understanding the alterations in the cell populations induced by the virus is pivotal and can help to combat HIV at the time of infection and above all, to prevent the establishment of viral reservoirs. In this review, we will describe the frequency and the subtypes of infected cells such as of monocytes, DCs, neutrophils, eosinophils, mast cells/basophils, NK cells, NKT cells and γδ T cells, and we discuss the possibility of cell-targeting strategies. Our aim is to consolidate the existing knowledge of the interaction between HIV and cells that constitute the innate immune response.

HLA-C levels impact natural killer cell subset distribution and function.

Differences in HLA-C expression are inversely correlated with HIV viral load set-point and slower progression to AIDS, linked to enhanced cytotoxic T cell immunity. Yet, beyond T cells, HLA-C serves as a dominant ligand for natural killer (NK) cell killer immunoglobulin-like receptors (KIR). Thus, we speculated that HLA-C expression levels may also impact NK activity, thereby modulating HIV antiviral control. Phenotypic and functional profiling was performed on freshly isolated PBMCs. HLA-C expression was linked to changes in NK subset distribution and licensing, particularly in HLA-C1/C1, KIR2DL3+2DL2-individuals. Moreover, high levels of HLA-C, were associated with reduced frequencies of anergic CD56neg NKs and lower frequencies of KIR2DL1/2/3+ NK cells, pointing to an HLA-C induced influence on the NK cell development in the absence of disease. In HIV infection, several spontaneous controllers, that expressed higher levels of HLA-C demonstrated robust NK-IFN-γ secretion in response to target cells, highlighting a second disease induced licensing phenotype. Thus this population study points to a potential role for HLA-C levels both in NK cell education and development.