Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy.

BACKGROUND: Conflicting results have been reported among studies of protease inhibitor (PI) use during pregnancy and preterm birth. Uncontrolled confounding by indication may explain some of the differences among studies. METHODS: In total, 777 human immunodeficiency virus (HIV)-infected pregnant women in a prospective cohort who were not receiving antiretroviral (ARV) treatment at conception were studied. Births <37 weeks gestation were reviewed, and deliveries due to spontaneous labor and/or rupture of membranes were identified. Risk of preterm birth and low birth weight (<2500 g) were evaluated by using multivariable logistic regression. RESULTS: Of the study population, 558 (72%) received combination ARV with PI during pregnancy, and a total of 130 preterm births were observed. In adjusted analyses, combination ARV with PI was not significantly associated with spontaneous preterm birth, compared to ARV without PI (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.70-2.12). Sensitivity analyses that included women who received ARV prior to pregnancy also did not identify a significant association (OR, 1.34; 95% CI, 0.84-2.16). Low birth weight results were similar. CONCLUSIONS: No evidence of an association between use of combination ARV with PI during pregnancy and preterm birth was found. Our study supports current guidelines that promote consideration of combination ARV for all HIV-infected pregnant women.

Cysteine proteinase-1 and cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron.

Dendrites often exhibit structural changes in response to local inputs. Although mechanisms that pattern and maintain dendritic arbors are becoming clearer, processes regulating regrowth, during context-dependent plasticity or after injury, remain poorly understood. We found that a class of Drosophila sensory neurons, through complete pruning and regeneration, can elaborate two distinct dendritic trees, innervating independent sensory fields. An expression screen identified Cysteine proteinase-1 (Cp1) as a critical regulator of this process. Unlike known ecdysone effectors, Cp1-mutant ddaC neurons pruned larval dendrites normally but failed to regrow adult dendrites. Cp1 expression was upregulated/concentrated in the nucleus during metamorphosis, controlling production of a truncated Cut homeodomain transcription factor. This truncated Cut, but not the full-length protein, allowed Cp1-mutant ddaC neurons to regenerate higher-order adult dendrites. These results identify a molecular pathway needed for dendrite regrowth after pruning, which allows the same neuron to innervate distinct sensory fields.

Relative Contributions of Prenylation and Postprenylation Processing in Cryptococcus neoformans Pathogenesis.

Prenyltransferase enzymes promote the membrane localization of their target proteins by directing the attachment of a hydrophobic lipid group at a conserved C-terminal CAAX motif. Subsequently, the prenylated protein is further modified by postprenylation processing enzymes that cleave the terminal 3 amino acids and carboxymethylate the prenylated cysteine residue. Many prenylated proteins, including Ras1 and Ras-like proteins, require this multistep membrane localization process in order to function properly. In the human fungal pathogen Cryptococcus neoformans, previous studies have demonstrated that two distinct forms of protein prenylation, farnesylation and geranylgeranylation, are both required for cellular adaptation to stress, as well as full virulence in animal infection models. Here, we establish that the C. neoformans RAM1 gene encoding the farnesyltransferase β-subunit, though not strictly essential for growth under permissive in vitro conditions, is absolutely required for cryptococcal pathogenesis. We also identify and characterize postprenylation protease and carboxyl methyltransferase enzymes in C. neoformans. In contrast to the prenyltransferases, deletion of the genes encoding the Rce1 protease and Ste14 carboxyl methyltransferase results in subtle defects in stress response and only partial reductions in virulence. These postprenylation modifications, as well as the prenylation events themselves, do play important roles in mating and hyphal transitions, likely due to their regulation of peptide pheromones and other proteins involved in development. IMPORTANCE Cryptococcus neoformans is an important human fungal pathogen that causes disease and death in immunocompromised individuals. The growth and morphogenesis of this fungus are controlled by conserved Ras-like GTPases, which are also important for its pathogenicity. Many of these proteins require proper subcellular localization for full function, and they are directed to cellular membranes through a posttranslational modification process known as prenylation. These studies investigate the roles of one of the prenylation enzymes, farnesyltransferase, as well as the postprenylation processing enzymes in C. neoformans. We demonstrate that the postprenylation processing steps are dispensable for the localization of certain substrate proteins. However, both protein farnesylation and the subsequent postprenylation processing steps are required for full pathogenesis of this fungus.