HIV Increases the Risk of Cigarette Smoke-Induced Emphysema Through MMP-9.

BACKGROUND: HIV is associated with an increased risk for emphysema. Matrix metalloproteinase 9 (MMP-9) is a lung tissue remodeling enzyme associated with emphysema. We previously found MMP-9 activity increases with increases in oxidative stress and that HIV increases alveolar oxidative stress. We hypothesized that HIV proteins would increase the risk of cigarette smoke-induced emphysema due to MMP-9. METHODS: HIV-1 transgenic rats and wild-type littermates were exposed to cigarette smoke or sham for 8 weeks. Lung compliance and histology were assessed. Bronchoalveolar lavage (BAL), primary alveolar macrophages (AM), and serum samples were obtained. A rat alveolar macrophage cell line was exposed to the HIV protein Tat, and MMP-9 levels were assessed by Western immunoblotting. MMP-9 protein expression and activity were assessed in AM from the HIV rat model by ELISA and cytoimmunofluoresence, respectively. Serum from human subjects with and without HIV and tobacco dependence was assessed for MMP-9 levels. RESULTS: MMP-9 expression was significantly increased in rat alveolar macrophages after Tat exposure. HIV-1 transgenic rats developed emphysema while wild-type littermates did not. MMP-9 expression was also increased in the serum, BAL, and AM of HIV-1 transgenic rats after exposure to cigarette smoke compared with wild-type rats. In parallel, serum samples from HIV+ smokers had higher levels of MMP-9 than subjects without HIV and those who did not smoke. CONCLUSION: The combination of HIV and cigarette smoke increases MMP-9 expression in experimental rat HIV models and human subjects. HIV and cigarette smoke both induce alveolar oxidative stress and thereby increase MMP-9 activity.

Building the evidence for hepatitis B vaccination programs for students and researchers working with biological samples in Indian Institutes of Higher Education.

BACKGROUND: Individuals working with biological samples in Indian universities are at risk for occupational exposure to hepatitis B virus (HBV) and may not be vaccinated. AIM: We documented the need for HBV vaccination in students and others, developed an institutional HBV vaccination program, delivered HBV vaccines, and then assessed the determinants of vaccine uptake. METHODS: Over a year, we conducted a prospective cohort study documenting the need for HBV vaccination in people working with biological materials in a major Indian institution, developed a HBV vaccination program, delivered HBV vaccines, and assessed determinants of vaccine uptake. In August 2018, a needs assessment determined exposure to blood, body fluids, and other potentially infectious material in the research setting, followed in September by a cross-sectional survey on HBV vaccination status. Institutional approval for vaccination followed in October, and vaccine clinics began in February 2019. In September, a follow-up survey investigated determinants of vaccine uptake. RESULTS: A total of 185 people participated in the baseline HBV vaccination status survey. Only 26% of students, staff, and faculty were fully vaccinated for HBV. Over 70% of the target group came forward for vaccination and >90% completed all doses. Getting vaccinated with peers strongly influenced vaccine uptake, as did availability of free vaccine, onsite clinics, and reminders. CONCLUSION: HBV vaccination programs for individuals at occupational risk are needed in Indian academic institutions beyond medical schools as part of institutional biosafety programs.

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain.

The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, ß-endorphin, within their endoplasmic reticulum (ER). When released into plasma, ß-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte ß-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low ß-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased ß-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased ß-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte ß-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte ß-endorphin is responsible for hypersensitivity in people with HIV.