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Extracellular vesicles (EVs) have been found to be released by any type of cell and can be retrieved in every circulating body fluid, namely blood (plasma, serum), saliva, milk, and urine. EVs were initially considered a cellular garbage disposal tool, but later it became evident that they are involved in intercellular signaling. There is evidence that viruses can use EV endocytic routes to enter uninfected cells and hijack the EV secretory pathway to exit infected cells, thus illustrating that EVs and viruses share common cell entry and biogenesis mechanisms. Moreover, EVs play a role in immune response against viral pathogens. EVs incorporate and spread both viral and host factors, thereby prompting or inhibiting immune responses towards them via a multiplicity of mechanisms. The involvement of EVs in immune responses, and their potential use as agents modulating viral infection, will be examined. Although further studies are needed, the engineering of EVs could package viral elements or host factors selected for their immunostimulatory properties, to be used as vaccines or tolerogenic tools in autoimmune diseases.

It is now well-accepted that Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC), can contribute to vaccine-elicited protection as well as post-infection control of HIV viremia. This picture was derived using a wide array of ADCC assays, no two of which are strictly comparable, and none of which is qualified at the clinical laboratory level. An earlier comparative study of assay protocols showed that while data from different ADCC assay formats were often correlated, they remained distinct in terms of target cells and the epitopes and antigen(s) available for recognition by antibodies, the effector cells, and the readout of cytotoxicity. This initial study warrants expanded analyses of the relationships among all current assay formats to determine where they detect overlapping activities and where they do not. Here we summarize knowns and unknowns of assaying ADCC against HIV-1.

Background This study is the first to describe major epidemiological trends and clinical characteristics among Israeli men who have sex with men (MSM), who are at a higher risk for HIV infection. Methods This retrospective study includes all individuals reported to the Israeli Ministry of Health with HIV and self-identified as MSM between 1981 and 2015. The incidence rates of HIV infection and AIDS-defining diseases were analyzed and Kaplan-Meier survival estimates were calculated from time of HIV infection notification to AIDS diagnosis and death across three consecutive periods representing antiretroviral treatment availability. Results The trend of increase in HIV incidence is similar to Western Europe, although Israeli rates are lower. Of 2052 HIV/AIDS Israeli MSM diagnosed during the follow-up, 296 (14.6%) developed AIDS. MSM constitute 28.4% of all HIV/AIDS cases and 41.5% of cases among men. Average times from HIV-notification until AIDS diagnosis were 15.5 [14.0–16.9], 16.0 [15.5–16.4], and 6.7 [6.7–6.8] years, within 1981–1996, 1997–2007, and 2008–2015, respectively. The HIV-incidence rate among Israeli MSM slightly declined from 2012, after peaking in 2011 at 6.2 per 100,000. Conclusions The recent reduction in HIV-incidence and in AIDS diagnoses among Israeli MSM is encouraging. Nevertheless, the disproportionate incidence of HIV among MSM requires sustained efforts to abate further infections.

Despite being highly preventable, cervical cancer is the fourth most common cancer and cause of cancer death in women globally. In low-income countries, cervical cancer is often the leading cause of cancer-related morbidity and mortality. Women living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome are at a particularly high risk of cervical cancer because of an impaired immune response to human papillomavirus, the obligate cause of virtually all cervical cancers. Globally, approximately 1 in 20 cervical cancers is attributable to HIV; in sub-Saharan Africa, approximately 1 in 5 cervical cancers is due to HIV. Here, the authors provide a critical appraisal of the evidence to date on the impact of HIV disease on cervical cancer risk, describe key methodologic issues, and frame the key outstanding research questions, especially as they apply to ongoing global efforts for prevention and control of cervical cancer. Expanded efforts to integrate HIV care with cervical cancer prevention and control, and vice versa, could assist the global effort to eliminate cervical cancer as a public health problem.

Background: We investigated the prevalence of HIV and human papilloma virus (HPV) infection in men with penile carcinoma. Method: This retrospective study investigated all men with penile carcinoma at the Universitas Academic Hospital in Bloemfontein, South Africa (January 2000–December 2008). Patients' age, HIV status, histological type of carcinoma and evidence of HPV infection were recorded. Statistical analyses included Student's t-test and Fisher's exact test where appropriate (2-tailed p-value < 0.05 indicated statistical significant). Results: Among 65 patients (mean age 50.9 years, range 37–69), the most common histological type was squamous cell carcinoma (80.0%). HIV status was known for 48 patients; 27 (56.2%) were HIV-positive. The mean age at presentation was 43.7 years (range 26–69) years in the HIV-positive and 57.2 years (range 26–89) years in the HIV-negative group. Approximately 55% of HIV-positive and 24% of HIV-negative patients showed histological evidence of HPV infection (p = 0.04). No significant difference was found with regard to histological type of carcinoma. Conclusion: Patients with penile carcinoma had a high prevalence of HIV infection. The HIV-positive group were significantly younger at presentation, with a higher prevalence of HPV infection, suggesting that HIV may contribute to HPV-associated penile cancer at a younger age.

Botswana is one of the HIV/AIDS hardest hit countries in Sub-Saharan Africa with a prevalence of 17.6 percent while incidence is estimated to be 2.9 percent. The average risk of HIV transmission after a percutaneous exposure to HIV-infected blood has been estimated to be approximately 0.3% posing a threat to health care workers. This has resulted in HIV post exposure prophylaxis (PEP) being very important in the healthcare setting. The aim of this study was to assess knowledge, attitudes and practices of health care workers towards HIV PEP. A cross-sectional study was conducted at Princes Marina Hospital (PMH) in Gaborone from the 26th March-2nd April 2014. Inclusion criteria- registered medical doctors and nurses. Collected sample size was 199. Data was collected using self-administered questionnaires. The majority of respondents 70.7% of the respondents had adequate knowledge about PEP, with 191(97.4%) of the study participants being aware of HIV PEP while 82.2% of the respondents had a positive attitude toward PEP. A significant number had been exposed 107(53.7%) to risky exposures. Of the exposed, 80(74.8%) took PEP, while 27(25.2%) did not take PEP. From the respondents that took PEP 21(26.6%) did not complete PEP, with 15(71.4%) quitting because of adverse side effects, 1(4.76%) assuming it was enough treatment and 1(4.76%) doubting drug efficacy. The participants were knowledgeable of the existence of HIV PEP and had a positive attitude toward the HIV PEP program. Although the participants were knowledgeable, they showed inadequate practices with regard to HIV PEP.

Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.

Background Human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is still among the leading causes of disease burden and mortality in sub-Saharan Africa (SSA), and the world is not on track to meet targets set for ending the epidemic by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United Nations Sustainable Development Goals (SDGs). Precise HIV burden information is critical for effective geographic and epidemiological targeting of prevention and treatment interventions. Age- and sex-specific HIV prevalence estimates are widely available at the national level, and region-wide local estimates were recently published for adults overall. We add further dimensionality to previous analyses by estimating HIV prevalence at local scales, stratified into sex-specific 5-year age groups for adults ages 15–59 years across SSA. Methods We analyzed data from 91 seroprevalence surveys and sentinel surveillance among antenatal care clinic (ANC) attendees using model-based geostatistical methods to produce estimates of HIV prevalence across 43 countries in SSA, from years 2000 to 2018, at a 5 × 5-km resolution and presented among second administrative level (typically districts or counties) units. Results We found substantial variation in HIV prevalence across localities, ages, and sexes that have been masked in earlier analyses. Within-country variation in prevalence in 2018 was a median 3.5 times greater across ages and sexes, compared to for all adults combined. We note large within-district prevalence differences between age groups: for men, 50% of districts displayed at least a 14-fold difference between age groups with the highest and lowest prevalence, and at least a 9-fold difference for women. Prevalence trends also varied over time; between 2000 and 2018, 70% of all districts saw a reduction in prevalence greater than five percentage points in at least one sex and age group. Meanwhile, over 30% of all districts saw at least a five percentage point prevalence increase in one or more sex and age group. Conclusions As the HIV epidemic persists and evolves in SSA, geographic and demographic shifts in prevention and treatment efforts are necessary. These estimates offer epidemiologically informative detail to better guide more targeted interventions, vital for combating HIV in SSA.

PurposeWhilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs).MethodsDissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition.ResultsIn a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study.ConclusionsThese results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient’s own home on a biweekly or less frequent basis.

Viruses have a dual nature: particles are “passive substances” lacking chemical energy transformation, whereas infected cells are “active substances” turning-over energy. How passive viral substances convert to active substances, comprising viral replication and assembly compartments has been of intense interest to virologists, cell and molecular biologists and immunologists. Infection starts with virus entry into a susceptible cell and delivers the viral genome to the replication site. This is a multi-step process, and involves the cytoskeleton and associated motor proteins. Likewise, the egress of progeny virus particles from the replication site to the extracellular space is enhanced by the cytoskeleton and associated motor proteins. This overcomes the limitation of thermal diffusion, and transports virions and virion components, often in association with cellular organelles. This review explores how the analysis of viral trajectories informs about mechanisms of infection. We discuss the methodology enabling researchers to visualize single virions in cells by fluorescence imaging and tracking. Virus visualization and tracking are increasingly enhanced by computational analyses of virus trajectories as well as in silico modeling. Combined approaches reveal previously unrecognized features of virus-infected cells. Using select examples of complementary methodology, we highlight the role of actin filaments and microtubules, and their associated motors in virus infections. In-depth studies of single virion dynamics at high temporal and spatial resolutions thereby provide deep insight into virus infection processes, and are a basis for uncovering underlying mechanisms of how cells function.