Publications

Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4 T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.

PURPOSE

To evaluate the incidence of intermediate-stage age-related macular degeneration (AMD) in patients with acquired immunodeficiency syndrome (AIDS).

DESIGN

Cohort study.

METHODS

Patients enrolled in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) underwent 5- and 10-year follow-up retinal photographs. Intermediate-stage AMD (AREDS stage 3) was determined from these photographs by graders at a centralized Reading Center, using the Age-Related Eye Disease Study-2 grading system. The incidence of AMD in LSOCA was compared with that in the Multi-Ethnic Study of Atherosclerosis (MESA), a Human Immunodeficiency Virus (HIV)-uninfected cohort, which used a similar photographic methodology.

RESULTS

The incidence of AMD in LSOCA was 0.65/100 person-years (PY). In a multivariate analysis the only significant risk factor for AMD in LSOCA was smoking; the relative risk vs never-smokers was 3.4 for former smokers (95% confidence interval [CI] 1.3, 9.5; P = .02) and 3.3 for current smokers (95% CI 1.1, 9.7; P = .03). Compared with the MESA cohort, the race/ethnicity- and sex-adjusted risk of AMD in LSOCA was 1.75 (95% CI 1.16, 2.64; P = .008), despite the fact that the mean age of the MESA cohort was 17 years greater than the LSOCA cohort (61 ± 9 years vs 44 ± 8 years).

CONCLUSIONS

Patients with AIDS have a 1.75-fold increased race- and sex-adjusted incidence of intermediate-stage AMD compared with that found in an HIV-uninfected cohort. This increased incidence is consistent with the increased incidence of other age-related diseases in antiretroviral-treated, immune-restored, HIV-infected persons when compared with HIV-uninfected persons.

OBJECTIVE

To evaluate whether low ratings of interactions with providers and health plans in 2013 were associated with increased systemic lupus erythematosus (SLE) damage in 2015.

METHODS

Data were derived from the Lupus Outcomes Study (LOS) annual surveys and include items from the Consumer Assessment of Health Plans and Interpersonal Processes of Care Scale measuring dimensions of health care interactions. We used ordinary least squares regression to model the change in disease damage over a 2-year period, 2013-2015, as a function of ratings of multiple dimensions of interactions with providers and health plans, with and without adjustment for demographic characteristics, socioeconomic status, and SLE and overall health status, and logistic regression to estimate the effect of the same matrix of variables on the probability of experiencing a minimum clinically important increase in damage.

RESULTS

There were 566 LOS respondents who were followed from 2013-2015 and who rated their providers and health plans in 2013. After adjustment, persons with SLE rating their providers poorly in patient-provider communication experienced a significantly greater accrual of disease damage (odds ratio [OR] 0.23 [95% confidence interval (95% CI) 0.09-0.38]) and were more likely to experience a minimum clinically important increase in damage (OR 2.35 [95% CI 1.25-4.39]). After adjustment, those rating their health plan poorly on care coordination experienced a significantly greater accrual of disease damage (OR 0.19 [95% CI 0.03-0.35]) and were more likely to experience a minimum clinically important increase in damage (OR 2.20 [95% CI 1.12-4.34]).

CONCLUSION

Poor patient-provider communication and care coordination may result in increased disease damage.

PURPOSE

Discussions between oncologists and advanced cancer patients (ACPs) may touch on the complex issue of clinical trial participation. Numerous initiatives have sought to improve the quality of these potentially difficult conversations. However, we have limited data about what ACPs know about clinical research as they enter such discussions as, to date, such research has focused on the period following informed consent. This study examines ACPs' understanding of clinical research in the treatment period before consent.

METHODS

We conducted in-depth interviews with adult ACPs with limited treatment options at four clinics in an academic medical center. So as not to influence patients' perspectives, interviewers probed patients' knowledge of clinical research only if the patient first brought up the topic. Interviews (40-60 min) were audio-recorded, transcribed, and analyzed thematically and via quantitative content analysis by an interdisciplinary team.

RESULTS

Of 78 patients recruited, 56 (72%) spontaneously brought up the topic of clinical research during interview and are included in this analysis. Qualitative thematic analysis and quantitative content analysis revealed that patients' knowledge varied in terms of (1) accuracy and (2) specificity (level of detail). ACPs who spoke with high specificity were not always accurate, and ACPs with accurate knowledge included both high- and low-specificity speakers.

CONCLUSIONS

ACPs' knowledge of clinical research is variable. Patients who can discuss the technical details of their care may or may not understand the broader purpose and procedures of clinical trials. Understanding this variability is important for improving patient-provider communication about clinical research and supporting efforts to provide individualized care for ACPs.