Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly

Selenium is a fascinating element that has a long history, most of which documents it as a deleterious element to health. In more recent years, selenium has been found to be an essential element in the diet of humans, all other mammals, and many other life forms. It has many health benefits that include, for example, roles in preventing heart disease and certain forms of cancer, slowing AIDS progression in HIV patients, supporting male reproduction, inhibiting viral expression, and boosting the immune system, and it also plays essential roles in mammalian development. Elucidating the molecular biology of selenium over the past 40 years generated an entirely new field of science which encompassed the many novel features of selenium. These features were (1) how this element makes its way into protein as the 21st amino acid in the genetic code, selenocysteine (Sec); (2) the vast amount of machinery dedicated to synthesizing Sec uniquely on its tRNA; (3) the incorporation of Sec into protein; and (4) the roles of the resulting Sec-containing proteins (selenoproteins) in health and development. One of the research areas receiving the most attention regarding selenium in health has been its role in cancer prevention, but further research has also exposed the role of this element as a facilitator of various maladies, including cancer.

Exacerbated AIDS progression by PD-1 blockade during therapeutic vaccination in chronically SIV-infected rhesus macaques after ART treatment interruption

The persistence of latent HIV-1-infected cells, named the latent reservoir, is the major barrier to HIV-1 eradication, and the formation and maintenance of latent reservoir might be exacerbated by activation of the immunoinhibitory pathway and dysfunction of CD8 + T cells during HIV-1 infection. Our previous findings demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred effective control of highly pathogenic SIVmac239 infection in rhesus macaques. However, to our surprise, herein we found that a therapeutic vaccination in combination with PD-1 blockade resulted in activation of the viral reservoir, faster viral rebound after treatment interruption, accelerated acquired immune deficiency syndrome (AIDS) progression and ultimately death in chronically SIV-infected macaques after ART treatment interruption. Our study further demonstrated that the SIV provirus was preferentially enriched in PD-1 + CD4 + T cells due to their susceptibility to viral entry, potent proliferation ability and inability to perform viral transcription. In addition, the viral latency was effectively reactivated upon PD-1 blockade. Together, these results suggest that PD-1 blockade may be a double-edged sword for HIV-1 immunotherapy, and they provide important insight for the rational design of immunotherapy strategies toward an HIV-1 cure. Importance As one of the most challenging public health problems, there is no clinically effective cure strategies against HIV-1 infection yet. We have demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred better control of highly pathogenic SIVmac239 infection in rhesus macaques. In the present study, to our surprise, PD-1 blockade during therapeutic vaccination accelerated the reactivation of latent reservoir and then AIDS progression in chronically SIV-infected macaques after ART treatment interruption. Our further study demonstrated that the latent SIV provirus was preferentially enriched in PD-1 + CD4 + T cells because of its susceptibility of viral entry, inhibition of SIV transcription and potent ability of proliferation, and the viral latency was effectively reactivated by PD-1 blockade. Therefore, PD-1 blockade might be a double-edged sword for AIDS therapy. These findings provoke extensive interests to further exploit novel therapeutic treatment against HIV-1 infection and other emerging infectious diseases.

Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States–African American or United States–European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.

Elevated levels and Clinical Association of Serum Cytokines in Untreated HIV-1 Infection

Background Human immunodeficiency virus type 1 (HIV-1) infection disturbs the balance of CD4+ T cells and monocytes in the immune system. In the early stage of infection, the virus stimulates the activation and proliferation of immune cells, induces the release of cytokines, destroys CD4+ T cells, and accelerates HIV-1 replication and AIDS progression. It is essential to explore cytokine changes after HIV-1 infection and further understand the underlying mechanism of HIV infection. Methods In this study, we enrolled 38 HIV-infected subjects and 30 healthy subjects. We measured and compared CD4+ T cell counts and the serum cytokine levels in different groups. Results Our results showed significantly higher serum levels of IL-1β, IL-2, IL-4, IL-7, IL-10, IL-17, IFN-γ, and TNF-α in HIV-infected patients. Higher levels of IL-6 and IL-17 were observed in the < 200/mL CD4+ T cell count group, and higher levels of IL-2 were observed in the CCR5-tropic HIV strain group. Conclusion In conclusion, we found that HIV infection-induced activation of the immune system and cytokines could predict the severity of HIV disease and regulate HIV infection and replication differently depending on the type of virus strain.

Associations of the Polymorphisms of the NHEJ Pathway Genes With HIV-1 Infection and Aids Progression Among Men Who Have Sex With Men in Northern China

Background: Men who have sex with men (MSM) are at high risk of HIV infection. Non-homologous end joining (NHEJ) pathway is the main way of double-stranded DNA break (DSB) repair in the higher eukaryotes, and can repair the DSB timely at any time in cell cycle. The objective of this study was to investigate the association of SNPs of the NHEJ pathway genes with susceptibility to HIV-1 infection and AIDS progression among MSM residing in northern China.Results: In the present study, a total of 481 HIV-1 seropositive men and 493 HIV-1 seronegative men were included. And genotyping of 22 SNPs in NHEJ pathway genes was performed using the SNPscanTM Kit. Our results disclosed significant associations of XRCC6 rs132770 and XRCC4 rs1056503 genotypes with susceptibility to HIV-1 infection. The generalized multifactor dimensionality reduction (GMDR) analysis found a significant SNP-SNP interaction between the XRCC6 and XRCC4 variants in the risk of HIV-1 infection. In stratified analysis, the positive effects of XRCC5 rs16855458 and LIG4 rs1805388 on the CD4+ T cell count and clinical phase of disease were validated.Conclusions: Our results confirmed that the NHEJ gene polymorphisms played an important role in HIV-1 infection and AIDS progression in the northern Chinese MSM population.

HIV-1 Uses Dynamic Podosomes for Entry into Macrophages

ABSTRACT Macrophages are one of the major targets of human immunodeficiency virus 1 (HIV-1) and play crucial roles in viral dissemination and persistence during AIDS progression. Here, we reveal the dynamic podosome-mediated entry of HIV-1 into macrophages. Inhibition of podosomes prevented HIV-1 entry into macrophages, while stimulation of podosome formation promoted viral entry. Single-virus tracking revealed the temporal and spatial mechanism of the dynamic podosome-mediated viral entry process. The core and ring structures of podosomes played complex roles in viral entry. The HIV coreceptor CCR5 was recruited to form specific clusters at the podosome ring, where it participated in viral entry. The podosome facilitated HIV-1 entry with a rotation mode triggered by dynamic actin. Our discovery of this novel HIV-1 entry route into macrophages, mediated by podosomes critical for cell migration and tissue infiltration, provides a new view of HIV infection and pathogenesis, which may assist in the development of new antiviral strategies. IMPORTANCE Macrophages are motile leukocytes and play critical roles in HIV-1 infection and AIDS progression. Podosomes, as small dynamic adhesion microdomains driven by the dynamic actin cytoskeleton, are mainly involved in cell migration of macrophages. Herein, we found that HIV-1 uses dynamic podosomes to facilitate its entry into macrophages. Single-virus imaging coupled with drug assays revealed the mechanism underlying the podosome-mediated route of HIV-1 entry into macrophages, including the dynamic relationship between the viral particles and the podosome core and ring structures, the CCR5 coreceptor. The dynamic podosome-mediated entry of HIV-1 into macrophages will be very significant for HIV-1 pathogenesis, especially for viral dissemination via macrophage migration and tissue infiltration. Thus, we report a novel HIV-1 entry route into macrophages mediated by podosomes, which extends our understanding of HIV infection and pathogenesis.

COMPLIANCE WITH ANTIRETROVIRAL THERAPY AMONG MSM AT CLINIC X, JAKARTA

Abstrak Latar belakang: Kepatuhan terapeutik di Indonesia masih di bawah 80 persen dan dapat mengakibatkan peningkatan insidensi infeksi usus protozoanal, perkembangan AIDS yang lebih cepat, resistensi obat, kegagalan pengobatan, dan penularan virus ke orang lain. Tujuan: Tujuan penelitian ini adalah untuk menggambarkan kepatuhan terhadap terapi antiretroviral pada LSL yang mencari pengobatan di klinik swasta dan menyelidiki faktor pendukung dan hambatan untuk retensi ART. Metode: Penelitian ini menggunakan metode penelitian kualitatif dan data yang dikumpulkan melalui wawancara mendalam. Subjek penelitian dipilih dengan menggunakan purposive sampling. Data dianalisis menggunakan analisis isi. Hasil: Informan berjumlah 7 orang, 4 ODHA, dan 3 petugas kesehatan. Hasilnya menunjukkan bahwa sebagian besar ODHA patuh dalam menggunakan terapi ARV dan mengikuti saran dokter. Faktor-faktor yang mendukung kepatuhan terhadap terapi ARV meliputi tingkat pendidikan, akses informasi, motivasi internal, hubungan pasien dengan dokter, dan dukungan sosial. Hoax, faktor yang terkait dengan pekerjaan, dan stigma adalah hambatan bagi orang yang hidup dengan HIV dalam mempertahankan kepatuhan terhadap terapi ARV. Kesimpulan: Kepatuhan optimal terhadap terapi ARV perlu dipertahankan dan ditingkatkan karena dinamis dan dipengaruhi oleh berbagai faktor. Intervensi berbasis teknologi direkomendasikan dalam memantau kepatuhan ODHA dalam terapi ARV. Kata Kunci: kepatuhan, terapi antiretroviral, hambatan, LSL, ODHA. Abstract Background: Therapeutic compliance in Indonesia was still below 80 percent and may resulted in increased incidence of protozoanal intestinal infection, faster AIDS progression, drug resistance, treatment failure, and transmission of the virus to others. Objective: The purpose of this study was to describe adherence to antiretroviral therapy among MSM who seek treatment at private clinics and investigate facilitators and barriers to ART retention. Method: This study used qualitative research methods and data collected through in-depth interview. The study subjects were selected using a purposive sampling. Data were analyzed using content analysis. Results: The informants were 7 people include 4 PLWHA and 3 health workers. The results showed that most ODHA were compliant in taking ARV therapy and following doctor's advice. Factors supported adherence to ARV therapy include levels of education, access to information, internal motivation, patient relationships with doctors, and social support. Hoaxes, work related factors, and stigma are barriers to people living with HIV in sustaining ARV therapy adherence. Conclusion: Optimal adherence to ARV therapy needs to be maintained and improved because it is dynamic and influenced by various factors. Technological interventions are recommended in monitoring PLWHA compliance in ARV therapy Keywords: adherence, antiretroviral therapy, barriers, MSM, PLWHA.

Examining HIV progression mechanisms via mathematical approaches

The progression of HIV infection to AIDS is unclear and under examined. Many mechanisms have been proposed, including a decline in immune response, increase in replication rate, involution of the thymus, syncytium inducing capacity, activation of the latently infected cell pool, chronic activation of the immune system, and the ability of the virus to infect other immune system cells. The significance of each mechanism in combination has not been studied. We develop a simple HIV viral dynamics model incorporating proposed mechanisms as parameters that are allowed to vary. In the entire parameter space, we derive two formulae for the basic reproduction number (R0) by considering the infection starting with a single infected CD4 T cell and a single virion, respectively. We show that both formulae are equivalent. We derive analytical conditions for the occurrence of backward and forward bifurcations. To investigate the influence of the proposed mechanisms to the HIV progression, we perform uncertainty and sensitivity analysis for all parameters and conduct a bifurcation analysis on all parameters that are shown to be significant, in combination, to explore various HIV/AIDS progression dynamics.