MDSC expansion during HIV infection: regulators, ART and immune reconstitution.

Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.

The Role of p53 in HIV Infection.

PURPOSE OF REVIEW: This review aims to elucidate the multifaceted role of the tumor suppressor protein p53 in the context of HIV infection. We explore how p53, a pivotal regulator of cellular processes, interacts with various facets of the HIV life cycle. Understanding these interactions could provide valuable insights into potential therapeutic interventions and the broader implications of p53 in viral infections. RECENT FINDINGS: Recent research has unveiled a complex interplay between p53 and HIV. Several reports have highlighted the involvement of p53 in restricting the replication of HIV within both immune and nonimmune cells. Various mechanisms have been suggested to unveil how p53 enforces this restriction on HIV replication. However, HIV has developed strategies to manipulate p53, benefiting its replication and evading host defenses. In summary, p53 plays a multifaceted role in HIV infection, impacting viral replication and disease progression. Recent findings underscore the importance of understanding the intricate interactions between p53 and HIV for the development of innovative therapeutic approaches. Manipulating p53 pathways may offer potential avenues to suppress viral replication and ameliorate immune dysfunction, ultimately contributing to the management of HIV/AIDS. Further research is warranted to fully exploit the therapeutic potential of p53 in the context of HIV infection.

The role of IL-1ß during human immunodeficiency virus type 1 infection.

Interleukin (IL)-1ß is a key innate cytokine that is essential for immune activation and promoting the inflammatory process. However, abnormal elevation in IL-1ß levels has been associated with unwanted clinical outcomes. IL-1ß is the most extensively studied cytokine among the IL-1 family of cytokines and its role in pathology is well established. During the course of human immunodeficiency virus type 1 (HIV-1) infection, the level of this proinflammatory cytokine is increased in different anatomical compartments, particularly in lymphatic tissues, and this elevation is associated with disease progression. The aim of this review is to address the pathological roles play by IL-1ß in the light of enhancing HIV-1 replication, driving immune cell depletion, and chronic immune activation. The role of IL-1ß in HIV-1 transmission (sexually or vertically 'from mother-to-child') will also be discussed. Additionally, the impact of the available antiretroviral therapy regimens on the levels of IL-1ß in HIV-1 treated patients is also discussed. Finally, we will provide a glance on how IL-1ß could be targeted as a therapeutic strategy.

T-cell evasion and invasion during HIV-1 infection: The role of HIV-1 Tat protein.

T-cell-mediated immune responses play indispensable roles in the defense against infectious pathogens including human immunodeficiency virus type 1 (HIV-1) which can establish a persistent infection that leads to many alterations in T-cell-mediated immunity. The latter include T-cell hyperactivation and depletion, both of which are essential for disease progression. Determining the factors and mechanisms pathways that lead to such abnormalities in T-cell mediated immunity during HIV-1 infection and ascertaining how the virus is able to evade immune responses elicited by T cells are critical for understanding the pathophysiology of HIV-1 infection, which in turn, could lead to new insights that may accelerate the development of novel and effective therapeutic strategies. To this end, we addressed the roles played by HIV-1 Tat protein, one of the first proteins to be expressed, in the pathogenesis of HIV-1 infection, focusing on the pathological effects of this protein in the cellular adaptive immune response in which T cells are intimately involved.

The clinical and prognostic significance of CMTM6/PD-L1 in oncology.

The recent discovery of CMTM6 and to a lesser extent CMTM4, two members of the chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family, as master positive regulators of PD-L1 expression, the primary ligand of programmed cell death 1 (PD-1), on tumor and immune cells has opened new horizons for investigating the role of CMTM6/CMTM4 in different aspects of oncology including their clinical and prognostic values in different cancer types. The absence of a specific review article addressing the available results about the clinical and prognostic roles of CMTM6 alone and/or in combination with PD-L1 in cancer has encouraged us to write this paper.

CMTM6 as a master regulator of PD-L1.

Immune checkpoint proteins, such as programmed cell death receptor 1 (PD-1) and its ligand (PD-L1), play critical roles in the pathology of chronic inflammatory pathological conditions, particularly cancer. In addition, the activation of PD-1/PD-L1 pathway is involved in mediating resistance to certain anti-cancer chemo- and immuno-therapeutics. Unfortunately, targeting the PD-1/PD-L1 pathway by the available anti-PD-1/PD-L1 drugs can benefit only a small proportion of cancer patients. Thus, studying the factors that regulate the expression of these immune checkpoint proteins is of central importance in this context. Recent investigations have identified CMTM6 and, to a lesser extent, CMTM4, as master regulators of PD-L1 expression in various cancer cells. Understanding the mechanisms by which such proteins upregulate the expression of PD-L1 in tumor cells, and determining the potential regulators of CMTM6 expression in different types of cancers will accelerate the development of new therapeutic targets and/or lead to the enhancement of the currently available PD-1/PD-L1 blockade therapies.

Anatomical Distribution of Myeloid-Derived Suppressor Cells During HIV Infection.

In recent years, expansion of myeloid-derived suppressor cells (MDSCs) has been reported to play a detrimental role in the pathogenesis of human immunodeficiency virus (HIV) infection. Much effort has been focused to comprehend the mechanisms and factors that regulate the expansion of such unwanted immune cell populations. Of particular interest has been the mechanisms by which MDSCs could contribute to the pathogenesis of HIV infection. So far, the studies have been restricted to MDSCs in the circulatory system of HIV patients, but not in other tissue compartments. In fact, lymphatic tissues/organs are the primary sites where HIV replication and immune depletion/dysfunction occur during the course of HIV infection. Therefore, investigating the anatomical distribution of MDSCs in such compartments is essential to understand the role that they play in the pathogenesis of HIV infection. Hence, we aim to shed light on the available literature about the anatomical distribution of MDSCs during HIV infection and compare it with the distribution of MDSCs in other pathological conditions, mainly cancer.

Myeloid-derived suppressor cells and the pathogenesis of human immunodeficiency virus infection.

There are several mechanisms by which human immunodeficiency virus (HIV) can mediate immune dysfunction and exhaustion during the course of infection. Chronic immune activation, after HIV infection, seems to be a key driving force of such unwanted consequences, which in turn worsens the pathological status. In such cases, the immune system is programmed to initiate responses that counteract unwanted immune activation, for example through the expansion of myeloid-derived suppressor cells (MDSCs). Although the expansion of immune suppressor cells in the setting of systemic chronic immune activation, in theory, is expected to contain immune activation, HIV infection is still associated with a remarkably high level of biomarkers of immune activation. Paradoxically, the expansion of immune suppressor cells during HIV infection can suppress potent anti-viral immune responses, which in turn contribute to viral persistence and disease progression. This indicates that HIV hijacks not only immune activation but also the immune regulatory responses to its advantage. In this work, we aim to pave the way to comprehend how such unwanted expansion of MDSCs could participate in the pathology of acute/primary and chronic HIV infection in humans, as well as simian immunodeficiency virus infection in rhesus macaques, according to the available literature.

The impact of MDSCs on the efficacy of preventive and therapeutic HIV vaccines.

In spite of four decades of research on human immunodeficiency virus (HIV), the virus remains a major health problem, affecting tens of millions of people around the world. As such, developing an effective preventive/protective and therapeutic vaccines against HIV are essential to prevent/limit the continuous spread of the virus as well as to control the disease progression and to completely eradicate the virus from HIV infected patients, respectively. There are several factors that have impeded the development of such vaccines, and we need to gain further insight into these factors in order to enhance our knowledge concerning the proper immune activation pathways in the hope of accelerating the development of the highly sought-after vaccine. Recently, new immune cell populations, namely the myeloid-derived suppressor cells (MDSCs), were added to the battle of HIV infection. Indeed, MDSCs seem to play a central role in determining the efficacy of therapeutic and preventive vaccines, especially because vaccines, in general, enhance immune responses, while as a potent immunosuppressor cell population, MDSCs, in turn, subvert and limit the activation of immune responses. Hence, in this work, we sought to address the role of MDSCs in the context of preventive/protective, as well as, therapeutic HIV vaccines.

Use of conditioned media (CM) and xeno-free serum substitute on human adipose-derived stem cells (ADSCs) differentiation into urothelial-like cells.

BACKGROUND: Congenital abnormalities, cancers as well as injuries can cause irreversible damage to the urinary tract, which eventually requires tissue reconstruction. Smooth muscle cells, endothelial cells, and urothelial cells are the major cell types required for the reconstruction of lower urinary tract. Adult stem cells represent an accessible source of unlimited repertoire of untransformed cells. AIM: Fetal bovine serum (FBS) is the most vital supplement in the culture media used for cellular proliferation and differentiation. However, due to the increasing interest in manufacturing xeno-free stem cell-based cellular products, optimizing the composition of the culture media and the serum-type used is of paramount importance. In this study, the effects of FBS and pooled human platelet (pHPL) lysate were assessed on the capacity of human adipose-derived stem cells (ADSCs) to differentiate into urothelial-like cells. Also, we aimed to compare the ability of both conditioned media (CM) and unconditioned urothelial cell media (UCM) to induce urothelial differentiation of ADCS in vitro. METHODS: ADSCs were isolated from human lipoaspirates and characterized by flow cytometry for their ability to express the most common mesenchymal stem cell (MSCs) markers. The differentiation potential was also assessed by differentiating them into osteogenic and adipogenic cell lineages. To evaluate the capacity of ADSCs to differentiate towards the urothelial-like lineage, cells were cultured with either CM or UCM, supplemented with either 5% pHPL, 2.5% pHPL or 10% FBS. After 14 days of induction, cells were utilized for gene expression and immunofluorescence analysis. RESULTS: ADSCs cultured in CM and supplemented with FBS exhibited the highest upregulation levels of the urothelial cell markers; cytokeratin-18 (CK-18), cytokeratin-19 (CK-19), and Uroplakin-2 (UPK-2), with a 6.7, 4.2- and a 2-folds increase in gene expression, respectively. Meanwhile, the use of CM supplemented with either 5% pHPL or 2.5% pHPL, and UCM supplemented with either 5% pHPL or 2.5% pHPL showed low expression levels of CK-18 and CK-19 and no upregulation of UPK-2 level was observed. In contrast, the use of UCM with FBS has increased the levels of CK-18 and CK-19, however to a lesser extent compared to CM. At the cellular level, CK-18 and UPK-2 were only detected in CM/FBS supplemented group. Growth factor analysis revealed an increase in the expression levels of EGF, VEGF and PDGF in all of the differentiated groups. CONCLUSION: Efficient ADSCs urothelial differentiation is dependent on the use of conditioned media. The presence of high concentrations of proliferation-inducing growth factors present in the pHPL reduces the efficiency of ADSCs differentiation towards the urothelial lineage. Additionally, the increase in EGF, VEGF and PDGF during the differentiation implicates them in the mechanism of urothelial cell differentiation.

Recent advances in myeloid-derived suppressor cell biology.

In recent years, studying the role of myeloid-derived suppressor cells (MDSCs) in many pathological inflammatory conditions has become a very active research area. Although the role of MDSCs in cancer is relatively well established, their role in non-cancerous pathological conditions remains in its infancy resulting in much confusion. Our objectives in this review are to address some recent advances in MDSC research in order to minimize such confusion and to provide an insight into their function in the context of other diseases. The following topics will be specifically focused upon: (1) definition and characterization of MDSCs; (2) whether all MDSC populations consist of immature cells; (3) technical issues in MDSC isolation, estimation and characterization; (4) the origin of MDSCs and their anatomical distribution in health and disease; (5) mediators of MDSC expansion and accumulation; (6) factors that determine the expansion of one MDSC population over the other; (7) the Yin and Yang roles of MDSCs. Moreover, the functions of MDSCs will be addressed throughout the text.

Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine.

Chronic immune activation and inflammation are unwanted consequences of many pathological conditions, since they could lead to tissue damage and immune exhaustion, both of which can worsen the pathological condition status. In fact, the immune system is naturally equipped with immunoregulatory cells that can limit immune activation and inflammation. However, chronic activation of downregulatory immune responses is also associated with unwanted consequences that, in turn, could lead to disease progression as seen in the case of cancer and chronic infections. Myeloid-derived suppressor cells (MDSCs) are now considered to play a pivotal role in the pathogenesis of different inflammatory pathological conditions, including different types of cancer and chronic infections. As a potent immunosuppressor cell population, MDSCs can inhibit specific and non-specific immune responses via different mechanisms that, in turn, lead to disease persistence. One such mechanism by which MDSCs can activate their immunosuppressive effects is accomplished by secreting copious amounts of immunosuppressant molecules such as interleukin-10 (IL-10). In this article, we will focus on the pathological role of MDSC expansion in chronic inflammatory conditions including cancer, sepsis/infection, autoimmunity, asthma and ageing, as well as some of the mechanisms by which MDSCs/IL-10 contribute to the disease progression in such conditions.

Harnessing Antibody-Dependent Cellular Cytotoxicity To Control HIV-1 Infection.

Passive administration of broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies (bNAbs) has been recently suggested as a promising alternative therapeutic approach for HIV-1 infection. Although the success behind the studies that used this approach has been attributed to the potency and neutralization breadth of anti-HIV-1 antibodies, several lines of evidence support the idea that specific antibody-dependent effector functions, particularly antibody-dependent cellular cytotoxicity (ADCC), play a critical role in controlling HIV-1 infection. In this review, we showed that there is a direct association between the activation of ADCC and better clinical outcomes. This, in turn, suggests that ADCC could be harnessed to control HIV-1 infection. To this end, we addressed the passive administration of bNAbs capable of selectively activating ADCC responses to HIV-1 patients. Finally, we summarized the potential barriers that may impede the optimal activation of ADCC during HIV-1 infection and provided strategic solutions to overcome these barriers.

The role of polymorphonuclear neutrophils during HIV-1 infection.

It is well-recognized that human immunodeficiency virus type-1 (HIV-1) mainly targets CD4+ T cells and macrophages. Nonetheless, during the past three decades, a huge number of studies have reported that HIV-1 can directly or indirectly target other cellular components of the immune system including CD8+ T cells, B cells, dendritic cells, natural killer cells, and polymorphonuclear neutrophils (PMNs), among others. PMNs are the most abundant leukocytes in the human circulation, and are known to play principal roles in the elimination of invading pathogens, regulating different immune responses, healing of injured tissues, and maintaining mucosal homeostasis. Until recently, little was known about the impact of HIV-1 infection on PMNs as well as the impact of PMNs on HIV-1 disease progression. This is because early studies focused on neutropenia and recurrent microbial infections, particularly, during advanced disease. However, recent studies have extended the investigation area to cover new aspects of the interactions between HIV-1 and PMNs. This review aims to summarize these advances and address the impact of HIV-1 infection on PMNs as well as the impact of PMNs on HIV-1 disease progression to better understand the pathophysiology of HIV-1 infection.

Mechanisms and Factors That Drive Extensive Human Immunodeficiency Virus Type-1 Hypervariability: An Overview.

The extensive hypervariability of human immunodeficiency virus type-1 (HIV-1) populations represents a major barrier against the success of currently available antiretroviral therapy. Moreover, it is still the most important obstacle that faces the development of an effective preventive vaccine against this infectious virus. Indeed, several factors can drive such hypervariability within and between HIV-1 patients. These factors include: first, the very low fidelity nature of HIV-1 reverse transcriptase; second, the extremely high HIV-1 replication rate; and third, the high genomic recombination rate that the virus has. All these factors together with the APOBEC3 proteins family and the immune and antiviral drugs pressures drive the extensive hypervariability of HIV-1 populations. Studying these factors and the mechanisms that drive such hypervariability will provide valuable insights that may guide the development of effective therapeutic and preventive strategies against HIV-1 infection in the near future. To this end, in this review, we summarized recent advances in this area of HIV-1 research.

Comparison of osteo/odontogenic differentiation of human adult dental pulp stem cells and stem cells from apical papilla in the presence of platelet lysate.

INTRODUCTION: Human dental pulp cells (DPSCs) and stem cells from apical papilla have been used for the repair of damaged tooth tissues. Human platelet lysate (PL) has been suggested as a substitute for fetal bovine serum (FBS) for large scale expansion of dental stem cells. However, biological effects and optimal concentrations of PL for proliferation and differentiation of human dental stem cells remain to be elucidated. METHODOLOGY: DPSCs and SCAP cells were isolated from impacted third molars of young healthy donors, at the stage of root development and identified by markers using flow cytometry. For comparison the cells were cultured in media containing PL (1%, 5% and 10%) and FBS, with subsequent induction for osteogenic/odontogenic differentiation. The cultures were analyzed for; morphology, growth characteristics, mineralization potential (Alizarin Red method) and differentiation markers using ELISA and real time -polymerase chain reaction (qPCR). RESULTS: The proliferation rates of DPSCs and SCAP significantly increased when cells were treated with 5% PL (7X doubling time) as compared to FBS. 5% PL also enhanced mineralized differentiation of DPSCs and SCAP, as indicated by the measurement of alkaline phosphatase activity, osteocalcin and osteopontin, calcium deposition and q-PCR. CONCLUSION: Our findings suggest that using 5% platelet lysate, proliferation and osteo/odontogenesis of DPSCs and SCAP for a short period of time (15 days), was significantly improved. This may imply its use as an optimum concentration for expansion of dental stem cells in bone regeneration.

Przhevalskiana silenus myiasis among slaughter goats in northern Jordan.

During the period December 1998-May 2000, 900 local goats slaughtered at the Irbid Abattoir (northern Jordan) were examined for the larval instars of Przhevalskiana silenus. Of 900 goats, 10% (95% CI: 9,13) were infested with P. silenus larvae. Only the second and third larval instars were seen. A multiple-regression analysis (with the error variance described by the negative-binomial function) suggested that infestation depended on the month of sampling, and that infestation with live larvae was associated with a poorer carcass. The percentage of infested goats and the mean monthly total number of larvae per goat peaked in samples taken in the autumn and winter. Larval numbers were highly aggregated: most animals had no larvae but the maximum was 69. Analysis of the pattern of aggregation suggested that the best model fit was one in which the larvae counts per goat varied with the monthly prevalence.

Oestrus ovis larval myiasis among goats in northern Jordan.

From December 1998 to December 1999, heads of 520 local goats slaughtered at the Irbid, Ramtha and Howarra Abattoirs (northern Jordan) were examined for the three larval instars (L(1)-L(3)) of Oestrus ovis. Of 520 heads, 126 (24%) were infested with O. ovis larvae. All three larval instars were observed in both sexes; all age groups were infested in each month of the year. The mean age of the goats sampled was 1.5 years. The numbers of parasites infesting hosts showed a significant (P<0.05) correlation with sheep age (r(sp)=0.31-0.42) for all three larval instars. The numbers of larvae in each host followed an overdispersed distribution, which fit a negative-binomial model (but not a Poisson distribution). There were more parasites recorded in the presence of purulent discharge or laryngitis, fewer in the presence of catarrhal discharge and no association with pharyngitis sinusitis, or rhinitis.