Livelihood Experiences and Adherence to HIV Antiretroviral Therapy among Participants in a Food Assistance Pilot in Bolivia: A Qualitative Study

Introduction

Health and development organizations increasingly promote livelihood interventions to improve health and economic outcomes for people living with HIV (PLHIV) receiving treatment with antiretroviral therapy (ART). In-depth understanding about how PLHIV make labor decisions in the context of treatment for HIV – and treatment decisions in the context of their livelihoods – is essential to guiding intervention design and developing hypotheses for future research on livelihoods and ART. However, few studies have explored the perspectives of PLHIV regarding integration of livelihoods and ART in urban, resource-limited settings.

Methods

Qualitative interviews explored the livelihood experiences of food insecure ART patients in four Bolivian cities (n = 211). Topics included work-related barriers to ART adherence, HIV-related barriers to work, and economic coping mechanisms. Themes were identified using content coding procedures, with two coders to maximize reliability.

Results

Participants reported complex economic lives often characterized by multiple economic activities, including both formal and informal labor. They struggled to manage ART treatment and livelihoods simultaneously, and faced a range of interpersonal and structural barriers. In particular, lack of HIV status disclosure, stigma, and discrimination were highly salient issues for study participants and likely to be unique to people with HIV, leading to conflict around requesting time off for clinic visits, resentment from co-workers about time off, and difficulties adhering to medication schedules. In addition, health system issues such as limited clinic hours or drug shortages exacerbated the struggle to balance economic activities with HIV treatment adherence.

Conclusions

Improved policy-level efforts to enforce existing anti-discrimination laws, reduce HIV-related stigma, and expand health services accessibility could mitigate many of the barriers discussed by our participants, improve adherence, and reduce the need for livelihoods interventions.     

DNA Vaccine Delivered by a Needle-Free Injection Device Improves Potency of Priming for Antibody and CD8+ T-Cell Responses after rAd5 Boost in a Randomized Clinical Trial

Background

DNA vaccine immunogenicity has been limited by inefficient delivery. Needle-free delivery of DNA using a CO₂-powered Biojector® device was compared to delivery by needle and syringe and evaluated for safety and immunogenicity.

Methods

Forty adults, 18–50 years, were randomly assigned to intramuscular (IM) vaccinations with DNA vaccine, VRC-HIVDNA016-00-VP, (weeks 0, 4, 8) by Biojector® 2000™ or needle and syringe (N/S) and boosted IM at week 24 with VRC-HIVADV014-00-VP (rAd5) with N/S at 10¹⁰ or 10¹¹ particle units (PU). Equal numbers per assigned schedule had low (≤500) or high (>500) reciprocal titers of preexisting Ad5 neutralizing antibody.

Results

120 DNA and 39 rAd5 injections were given; 36 subjects completed follow-up research sample collections. IFN-γ ELISpot response rates were 17/19 (89%) for Biojector® and 13/17 (76%) for N/S delivery at Week 28 (4 weeks post rAd5 boost). The magnitude of ELISpot response was about 3-fold higher in Biojector® compared to N/S groups. Similar effects on response rates and magnitude were observed for CD8+, but not CD4+ T-cell responses by ICS. Env-specific antibody responses were about 10-fold higher in Biojector-primed subjects.

Conclusions

DNA vaccination by Biojector® was well-tolerated and compared to needle injection, primed for greater IFN-γ ELISpot, CD8+ T-cell, and antibody responses after rAd5 boosting.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00109629","term_id":"NCT00109629"}}NCT00109629     

H3K56me3 Is a Novel,Conserved Heterochromatic Mark That Largely but Not Completely Overlaps with H3K9me3 in Both Regulation and Localization

Histone lysine (K) methylation has been shown to play a fundamental role in modulating chromatin architecture and regulation of gene expression. Here we report on the identification of histone H3K56, located at the pivotal, nucleosome DNA entry/exit point, as a novel methylation site that is evolutionary conserved. We identify trimethylation of H3K56 (H3K56me3) as a modification that is present during all cell cycle phases, with the exception of S-phase, where it is underrepresented on chromatin. H3K56me3 is a novel heterochromatin mark, since it is enriched at pericentromeres but not telomeres and is thereby similar, but not identical, to the localization of H3K9me3 and H4K20me3. Possibly due to H3 sequence similarities, Suv39h enzymes, responsible for trimethylation of H3K9, also affect methylation of H3K56. Similarly, we demonstrate that trimethylation of H3K56 is removed by members of the JMJD2 family of demethylases that also target H3K9me3. Furthermore, we identify and characterize mouse mJmjd2E and its human homolog hKDM4L as novel, functionally active enzymes that catalyze the removal of two methyl groups from trimethylated H3K9 and K56. H3K56me3 is also found in C. elegans, where it co-localizes with H3K9me3 in most, but not all, tissues. Taken together, our findings raise interesting questions regarding how methylation of H3K9 and H3K56 is regulated in different organisms and their functional roles in heterochromatin formation and/or maintenance.     

Systemic Inflammation in Non-Demented Elderly Human Subjects: Brain Microstructure and Cognition

The purpose of this study was to test the hypothesis that higher levels of systemic inflammation in a community sample of non-demented subjects older than seventy years of age are associated with reduced diffusion anisotropy in brain white matter and lower cognition. Ninety-five older persons without dementia underwent detailed clinical and cognitive evaluation and magnetic resonance imaging, including diffusion tensor imaging. Systemic inflammation was assessed with a composite measure of commonly used circulating inflammatory markers (C-reactive protein and tumor necrosis factor-alpha). Tract-based spatial statistics analyses demonstrated that diffusion anisotropy in the body and isthmus of the corpus callosum was negatively correlated with the composite measure of systemic inflammation, controlling for demographic, clinical and radiologic factors. Visuospatial ability was negatively correlated with systemic inflammation, and diffusion anisotropy in the body and isthmus of the corpus callosum was shown to mediate this association. The findings of the present study suggest that higher levels of systemic inflammation may be associated with lower microstructural integrity in the corpus callosum of non-demented elderly individuals, and this may partially explain the finding of reduced higher-order visual cognition in aging.     

Effect of Immune Reconstitution on the Incidence of HIV-Related Hodgkin Lymphoma

Background

The incidence of Hodgkin lymphoma (HL) has increased since introduction of combined antiretroviral therapy (cART). While HIV-related HL is highly associated with EBV, the causes underlying the rising incidence remain unclear. The aim of this study was to evaluate the effect of immune reconstitution on HL incidence among a cohort of HIV-infected male veterans ever receiving cART.

Methods

We performed a retrospective cohort study utilizing data from the Veterans Affairs HIV Clinical Case Registry from 1985-2010. HL cases were identified using ICD-9 codes (201.4-9). Poisson regression was conducted to evaluate relationships between cART-related immunologic measures (e.g., nadir CD4 before cART, time-updated CD4, % time undetectable HIV RNA) and HL incidence. Additionally, we examined CD4 change after cART initiation.

Results

31,056 cART users contributed 287,256 person-years and 196 HL cases (IR=6.8/10,000 person-years). Rate of CD4 increase after cART was worse among HL cases than non-cases (p<0.05). In multivariate regression, HL risk was elevated among veterans with recent CD4 200-350 cells/µL (IRR=1.67, 95%CI=1.16-2.40) and <200 cells/µL (IRR=1.61, 95%CI=1.09-2.39), compared to >350 cells/µL. HL risk was lower among veterans with >80% time undetectable HIV RNA (IRR=0.57, 95%CI=0.35-0.92) and 40-80% undetectable (IRR=0.68, 95%CI=0.47-0.99), compared to <40% undetectable. HL risk was higher in the first 12 months (IRR=2.02, 95%CI=1.32-3.10) and 12-24 months (IRR=1.75, 95%CI=1.16-2.64) after cART initiation, compared to >36 months.

Conclusion

These data highlight immunosuppression and poor viral control may increase HL risk, specifically during immune reconstitution in the interval post cART initiation. Findings suggest an immune reconstitution type mechanism in HIV-related HL development.     

Plant hemoglobins may be maintained in functional form by reduced flavins in the nuclei,and confer differential tolerance to nitro‐oxidative stress

The heme of bacteria, plant and animal hemoglobins (Hbs) must be in the ferrous state to bind O₂ and other physiological ligands. Here we have characterized the full set of non‐symbiotic (class 1 and 2) and ‘truncated’ (class 3) Hbs of Lotus japonicus. Class 1 Hbs are hexacoordinate, but class 2 and 3 Hbs are pentacoordinate. Three of the globins, Glb1‐1, Glb2 and Glb3‐1, are nodule‐enhanced proteins. The O₂ affinity of Glb1‐1 (50 pm ) was the highest known for any Hb, and the protein may function as an O₂ scavenger. The five globins were reduced by free flavins, which transfer electrons from NAD(P)H to the heme iron under aerobic and anaerobic conditions. Class 1 Hbs were reduced at very fast rates by FAD, class 2 Hbs at slower rates by both FMN and FAD, and class 3 Hbs at intermediate rates by FMN. The members of the three globin classes were immunolocalized predominantly in the nuclei. Flavins were quantified in legume nodules and nuclei, and their concentrations were sufficient to maintain Hbs in their functional state. All Hbs, except Glb1‐1, were expressed in a flavohemoglobin‐deficient yeast mutant and found to confer tolerance to oxidative stress induced by methyl viologen, copper or low temperature, indicating an anti‐oxidative role for the hemes. However, only Glb1‐2 and Glb2 afforded protection against nitrosative stress induced by S‐nitrosoglutathione. Because this compound is specifically involved in transnitrosylation reactions with thiol groups, our results suggest a contribution of the single cysteine residues of both proteins in the stress response.     

Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators

The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.