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.

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.

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.

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.

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.