The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip technology to obtain a more complete description of pineal cell biology. The effort revealed that 604 genes (1,268 probe sets) with Entrez Gene identifiers are differentially expressed greater than 2-fold between midnight and mid-day (false discovery rate <0.20). Expression is greater at night in ϳ70%. These findings were supported by the results of radiochemical in situ hybridization histology and quantitative real time-PCR studies. We also found that the regulatory mechanism controlling the night/ day changes in the expression of most genes involves norepinephrine-cyclic AMP signaling. Comparison of the pineal gene expression profile with that in other tissues identified 334 genes (496 probe sets) that are expressed greater than 8-fold higher in the pineal gland relative to other tissues. Of these genes, 17% are expressed at similar levels in the retina, consistent with a common evolutionary origin of these tissues. Functional categorization of the highly expressed and/or night/day differentially expressed genes identified clusters that are markers of specialized functions, including the immune/inflammation response, melatonin synthesis, photodetection, thyroid hormone signaling, and diverse aspects of cellular signaling and cell biology. These studies produce a paradigm shift in our understanding of the 24-h dynamics of the pineal gland from one focused on melatonin synthesis to one including many cellular processes.A defining feature of the pineal gland is a 24-h rhythm in melatonin synthesis. Melatonin provides vertebrates with a circulating signal of time and is essential for optimal integration of physiological functions with environmental lighting on a daily and seasonal basis (1-4).The melatonin rhythm in mammals is driven by a circadian clock located in the suprachiasmatic nucleus (SCN), 13 which is hard-wired to the pineal gland by a polysynaptic pathway that courses through central and peripheral neuronal structures. The pineal gland is innervated by projections from the superior cervical ganglia (SCG) in the form of a dense network of catecholamine-containing sympathetic fibers. Activation of the SCN 3 pineal pathway occurs at night and results in the release

IntroductionThe complex life cycle of HIV-1 involves critical functional interactions with CD4 ϩ host-cell factors. In addition to CD4 ϩ T cells, CD4 ϩ CCR5 ϩ macrophages represent a primary target and host of HIV-1. Infected macrophages replicate copious amounts of virus at their surface and at intracellular membranes where the virions accumulate in vesicles. 1 Macrophages are not typically subject to viral-induced death and may persist as reservoirs of virus in tissues for long periods of time. 2,3 In addition, infected macrophages may be resistant to antiviral agents, 3-6 and the unique attributes and factors that are enabling for this persistent viral host remain elusive. Critically, all monocytic cells are neither equally permissive to HIV-1 nor supportive of the viral life cycle. In vitro or in vivo, dendritic cells (DCs) may or may not become infected, depending on maturational status 7 ; peripheral-blood monocytes are nearly impervious (Ͻ 1% HIV-1 DNA ϩ ) 8,9 ; and of longstanding interest is the enhanced susceptibility of macrophages to HIV-1 compared with immature monocytes, the basis of which remains a mystery. The fact that macrophages, in culture and in tissues, are more susceptible to infection than monocytes cannot be attributed to levels of membrane CD4 or HIV-1 coreceptor expression 10 or multiple other criteria that have been considered. 11 This fundamental question has obvious significance in that if the monocyte-resistance factor(s) can be identified, opportunities may emerge for manipulating susceptible myeloid populations to impose a restrictive barrier to HIV-1. Limited evidence supports an early postentry block that occurs in association with or shortly after reverse transcription (RT). 8 Beyond the well-established CD4 and CCR5/CXCR4 entry requirements, recent evidence implicates additional membrane and intracellular factors that influence early host-cell responsiveness to productive infection. [11][12][13][14][15][16][17] Among the potential innate intracellular viral antagonists, initially characterized in T cells 18 and more recently in monocytes, 19,20 are cytidine deaminases that edit viral RNA and mutate DNA. These cytoplasmic apolipoprotein B mRNA-editing enzyme catalytic polypeptidelike (APOBEC) subunits, particularly APOBEC3G (hA3G), become incorporated into virions, leading to mutation of nascent HIV-1 DNA formed during reverse transcription and its subsequent degradation. 18,21,22 HIV-1, in turn, inhibits hA3G via HIV-1-encoded viral infectivity factor (Vif)-dependent and -independent pathways to thwart this antiviral defense within the target cell. Vif not only facilitates 26S proteasome-mediated degradation of hA3G but also diminishes its synthesis to collectively exclude hA3G incorporation into the budding virions. [23][24][25] Nonetheless, whether differential HIV-1 susceptibility in myeloid populations could be attributed to constitutively expressed hA3G or any other components of this defensive superfamily had not been addressed.In this study, by oligonucleotide microarr...

Infection of CD4