HIV-1 Transmission linkages among persons with incident infection to inform public health surveillance

Background: We evaluated features of HIV transmission networks involving persons diagnosed during incident HIV infection (IHI) to assess network-based opportunities to curtail onward transmission. Methods: Transmission networks were constructed using partial pol sequences reported to North Carolina surveillance among persons with recent (2014–2018) and past (90 days prior to an IHI were further characterized. We assessed named partner outcomes among IHI index persons using contact tracing data. Findings: Of 4,405 HIV diagnoses 2014–2018 with sequences, there were 323 (7%) IHI index persons; most were male (88%), Black (65%), young (68% <30 years), and reported sex with men (MSM) risk (79%). Index persons were more likely to be cluster members compared to non-index persons diagnosed during the same period (72% vs. 49%). In total, 162 clusters were identified involving 233 IHI, 577 recent diagnoses, and 163 past diagnoses. Most IHI cases (53%) had viral linkages to ≥1 previously diagnosed person without evidence of HIV viral suppression in the year prior to the diagnosis of the IHI index. In contact tracing, only 53% IHI cases named an HIV-positive contact, resulting in 0.5 previously diagnosed persons detected per IHI investigated. When combined with viral analyses, the detection rate of viremic previously diagnosed persons increased to 1.3. Interpretation: Integrating public health with molecular epidemiology, revealed that more than half of IHI have viral links to persons with previously diagnosed unsuppressed HIV infection which was largely unrecognized by traditional contact tracing. Enhanced partner services to support engagement and retention in HIV care and improved case finding supported by rapid phylogenetic analysis are tools to substantially reduce onward HIV transmission

Upregulation of astrocytic and microglial markers precedes late onset neurodegenerative changes in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis (platform presentation)

Up regulation of astrocytic and microglial markers precedes late onset neuro-degenerative changes in the Cln3–/– mouse model of juvenile neuronal ceroid lipofuscinosis Introduction: Mouse models of neuronal ceroid lipofuscinosis (NCL) exhibit many features of the human disorder,with widespread regional atrophy and significant loss of GABAergic interneurones in the hippocampus and cortex. Reactive gliosis is a characteristic of all forms of NCL, but it is unclear whether these events precede or are triggered by neuronal loss. Material and methods: Detailed morphological characterization and quantitative image analysis of the CLN3 null mutant (Cln3–/–) mouse model of juvenile NCL (JNCL). Results: Detailed morphological characterization revealed a delayed onset neurodegenerative phenotype with no significant regional atrophy, but with widespread significant loss of hippocampal interneurones that was evident at 14 months of age. Quantitative image analysis demonstrated an early up-regulation of markers of astrocytic and microglial activation in presymptomatic Cln3–/– mice at 5 months of age. These events take place several months before significant neuropathological changes occur, but are transient in nature and are less prominent at 14 months of age. Conclusion: These data provide evidence for glial responses early in JNCL pathogenesis, but it will be important to determine the relative significance of these events during disease progression

Increased cortical synaptic activation of TrkB and downstream signaling markers in a mouse model of Down Syndrome

Down Syndrome (DS), trisomy 21, is characterized by synaptic abnormalities and cognitive deficits throughout the lifespan and with development of Alzheimer’s disease (AD) neuropathology and progressive cognitive decline in adults. Synaptic abnormalities are also present in the Ts65Dn mouse model of DS, but which synapses are affected and the mechanisms underlying synaptic dysfunction are unknown. Here we show marked increases in the levels and activation status of TrkB and associated signaling proteins in cortical synapses in Ts65Dn mice. Proteomic analysis at the single synapse level of resolution using array tomography (AT) uncovered increased colocalization of activated TrkB with signaling endosome related proteins, and demonstrated increased TrkB signaling. The extent of increases in TrkB signaling differed in each of the cortical layers examined and with respect to the type of synapse, with the most marked increases seen in inhibitory synapses. These findings are evidence of markedly abnormal TrkB-mediated signaling in synapses. They raise the possibility that dysregulated TrkB signaling contributes to synaptic dysfunction and cognitive deficits in DS