We investigated whether angiotensin II receptor blockers and angiotensin converting enzyme inhibitors were associated with risk of mortality or inpatient hospitalization for patients with dementia compared to other antihypertensive medications. We extracted a clinical cohort of 6,290 patients with dementia from the United Kingdom General Practice Research Database, prescribed antihypertensive medication at diagnosis of dementia with around 10 years follow-up. Using survival analysis we estimated associations of exposure to antihypertensive medication with subsequent hospitalization and mortality risk, stratified by dementia type (Alzheimer's disease, vascular and other dementias). Angiotensin converting enzyme inhibitors (but not angiotensin II receptor blockers) were associated with an increased risk of mortality in patients with Alzheimer's disease (adjusted hazard ratio: 1.19; 95% CI 1.07, 1.33, p = 0.002), but no convincing evidence of increased hospitalization. Angiotensin II receptor blockers were inversely associated with hospitalization for any form of dementia, but after adjustment for covariates, these associations became consistent with chance. Further evidence is required to either support or refute the observation that exposure to angiotensin converting enzyme inhibitors in patients with dementia is associated with increased mortality.

Background: After viral fusion with the cell membrane, the conical capsid of HIV-1 disassembles by a process called uncoating. Previously we have utilized the CsA washout assay, in which TRIM-CypA mediated restriction of viral replication is used to detect the state of the viral capsid, to study the kinetics of HIV-1 uncoating in owl monkey kidney (OMK) and HeLa cells. Here we have extended this analysis to the human microglial cell lines CHME3 and C20 to characterize uncoating in a cell type that is a natural target of HIV infection. Methods: The CsA washout was used to characterize uncoating of wildtype and capsid mutant viruses in CHME3 and C20 cells. Viral fusion assays and nevirapine addition assays were performed to relate the kinetics of viral fusion and reverse transcription to uncoating. Results: We found that uncoating initiated within the first hour after viral fusion and was facilitated by reverse transcription in CHME3 and C20 cells. The capsid mutation A92E did not significantly alter uncoating kinetics. Viruses with capsid mutations N74D and E45A decreased the rate of uncoating in CHME3 cells, but did not alter reverse transcription. Interestingly, the second site suppressor capsid mutation R132T was able to rescue the uncoating kinetics of the E45A mutation, despite having a hyperstable capsid. Conclusions: These results are most similar to previously observed characteristics of uncoating in HeLa cells and support the model in which uncoating is initiated by early steps of reverse transcription in the cytoplasm. A comparison of the uncoating kinetics of CA mutant viruses in OMK and CHME3 cells reveals the importance of cellular factors in the process of uncoating. The E45A/R132T mutant virus specifically suggests that disrupted interactions with cellular factors, rather than capsid stability, is responsible for the delayed uncoating kinetics seen in E45A mutant virus. Future studies aimed at identifying these factors will be important for understanding the process of uncoating and the development of interventions to disrupt this process.

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