HIV Populations Are Large and Accumulate High Genetic Diversity in Nonlinear Fashion.

HIV Populations are Large and Accumulate High Genetic Diversity in Nonlinear Fashion.

J Virol. 2013 May 15;
Maldarelli F, Kearney M, Palmer S, Stephens R, Mican J, Polis MA, Davey RT, Kovacs J, Shao W, Rock-Kress D, Metcalf JA, Rehm C, Greer SE, Lucey DL, Danley K, Alter H, Mellors JW, Coffin JM

HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence, and to estimate replicating population sizes in a group of treatment naive HIV-infected individuals sampled at single (N=22) or multiple, longitudinal time points (N=11). Analysis of single genome sequences (SGS) revealed non-linear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were slow relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift. HubMed – drug

Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats.

J Neurosci. 2013 May 15; 33(20): 8650-67
Wells CE, Amos DP, Jeewajee A, Douchamps V, Rodgers J, O’Keefe J, Burgess N, Lever C

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion. HubMed – drug

Genetic reconstruction of dopamine d1 receptor signaling in the nucleus accumbens facilitates natural and drug reward responses.

J Neurosci. 2013 May 15; 33(20): 8640-9
Gore BB, Zweifel LS

The dopamine D1 receptor (D1R) facilitates reward acquisition and its alteration leads to profound learning deficits. However, its minimal functional circuit requirement is unknown. Using conditional reconstruction of functional D1R signaling in D1R knock-out mice, we define distinct requirements of D1R in subregions of the nucleus accumbens (NAc) for specific dimensions of reward. We demonstrate that D1R expression in the core region of the NAc (NAc(Core)), but not the shell (NAc(Shell)), enhances selectively a unique form of pavlovian conditioned approach and mediates D1R-dependent cocaine sensitization. However, D1R expression in either the NAc(Core) or the NAc(Shell) improves instrumental responding for reward. In contrast, neither NAc(Core) nor NAc(Shell) D1R is sufficient to promote motivation to work for reward in a progressive ratio task or for motor learning. These results highlight dissociated circuit requirements of D1R for dopamine-dependent behaviors. HubMed – drug