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.