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Alternative paths in HIV-1 targeted human signal transduction pathways.

ABSTRACT: Human immunodeficiency virus-1 (HIV-1) has a minimal genome of only 9 genes, which encode 15 proteins. HIV-1 thus depends on the human host for virtually every aspect of its life cycle. The universal language of communication in biological systems, including between pathogen and host, is via signal transduction pathways. The fundamental units of these pathways are protein protein interactions. Understanding the functional significance of HIV-1, human interactions requires viewing them in the context of human signal transduction pathways.Integration of HIV-1, human interactions with known signal transduction pathways indicates that the majority of known human pathways have the potential to be effected through at least one interaction with an HIV-1 protein at some point during the HIV-1 life cycle. For each pathway, we define simple paths between start points (i.e. no edges going into a node) and end points (i.e. no edges leaving a node). We then identify the paths that pass through human proteins that interact with HIV-1 proteins. We supplement the combined map with functional information, including which proteins are known drug targets and which proteins contribute significantly to HIV-1 function as revealed by recent siRNA screens. We find that there are often alternative paths starting and ending at the same proteins but circumventing the intermediate steps disrupted by HIV-1.A mapping of HIV-1, human interactions to human signal transduction pathways is presented here to link interactions with functions. We proposed a new way of analyzing the virus host interactions by identifying HIV-1 targets as well as alternative paths bypassing the HIV-1 targeted steps. This approach yields numerous experimentally testable hypotheses on how HIV-1 function may be compromised and human cellular function restored by pharmacological approaches. We are making the full set of pathway analysis results available to the community.

SUBMITTER: Balakrishnan S

PROVIDER: S-EPMC2788384 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Alternative paths in HIV-1 targeted human signal transduction pathways.

Balakrishnan Sivaraman S Tastan Oznur O Carbonell Jaime J Klein-Seetharaman Judith J

BMC genomics 20091203

<h4>Background</h4>Human immunodeficiency virus-1 (HIV-1) has a minimal genome of only 9 genes, which encode 15 proteins. HIV-1 thus depends on the human host for virtually every aspect of its life cycle. The universal language of communication in biological systems, including between pathogen and host, is via signal transduction pathways. The fundamental units of these pathways are protein protein interactions. Understanding the functional significance of HIV-1, human interactions requires view ...[more]

PMID: 19958495

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Project description:IntroductionThe local environment of the fallopian tube represents the optimal conditions for reproductive processes. To maintain tissue homeostasis, signal transduction pathways are thought to play a pivotal role. Enhancing our understanding of functional signal transduction pathway activity is important to be able to clarify the role of aberrant signal transduction pathway activity leading to female subfertility and other tubal diseases. Therefore, in this study we investigate the influence of the hormonal cycle on the activity of key signal transduction pathways in the fimbrial epithelium of morphologically normal fallopian tubes.Material and methodsWe included healthy pre- (n = 17) and postmenopausal (n = 8) patients who had surgical interventions for benign gynecologic conditions. Histologic sections of the fallopian tubes were reviewed by two pathologists and, for the premenopausal patients, hormone serum levels and sections of the endometrium were examined to determine the hormonal phase (early follicular [n = 4], late follicular [n = 3], early luteal [n = 5], late luteal [n = 5]). After laser capture microdissection, total mRNA was extracted from the fimbrial epithelium and real-time quantitative reverse transcription-PCR was performed to determine functional signal transduction pathway activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor-beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways.ResultsThe early luteal phase demonstrated high AR and ER pathway activity in comparison with the late luteal phase (p = 0.016 and p = 0.032, respectively) and low PI3K activity compared with the late follicular phase (p = 0.036), whereas the late luteal phase showed low activity of HH and Wnt compared with the early follicular phase (both p = 0.016). Signal transduction pathway activity in fimbrial epithelium from postmenopausal patients was most similar to the early follicular and/or late luteal phase with regard to the AR, ER and PI3K pathways. Wnt pathway activity in postmenopausal patients was comparable to the late follicular and early luteal phase. We observed no differences in HH and TGF-β pathway activity between pre- and postmenopausal samples. The cyclic changes in signal transduction pathway activity suggest a stage-specific function which may affect the morphology and physiology of the human fallopian tube.ConclusionsWe demonstrated cyclic changes in activity of the AR, ER, PI3K, HH and Wnt pathways throughout the hormonal cycle.

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Alternative paths in HIV-1 targeted human signal transduction pathways.

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Alternative paths in HIV-1 targeted human signal transduction pathways.

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