Prostatic acidic phosphatase (PAP) Enhances HIV Infection

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Münch J et al. published a paper regarding how semen can promote the HIV (human immunodeficiency virus) infection on Cell last December. Inspired by the idea that screening of peptide libraries from human body fluids is a useful approach to discover unknown molecules modulating HIV-1 infection, they turned their attention to semen, an indispensible factor in all STDs (Sexually Transmitted Diseases).

Pooling 183 ml of human semen, they purified and obtained fractions by cation-exchange separation, followed by reversed-phase (RP) chromatography. Then each fraction was tested for respective infectivity for HIV-1 by mixing each fraction with HIV virons to infect engineered cell lines expressed CD4 / CXCR4 / CCR5. They found a fraction, which was then further recognized as a segment of PAP (prostatic acidic phosphatase) by mass spectrometry (MS), significantly increase infectivity of HIV.

They found these PAP fragment are active for HIV infection only after the solutions turned turbid either spontaneously or after agitation. Thioflavin T, Congo red staining, X-ray powder diffraction, and even electron microscopy finally clarified that these PAP fragment formed amyloid fibrils. These fibrils, termed SEVI (Semen-derived Enhancer of Virus Infection), was postulated to capture HIV virons, promote viral attachment to the target cell, and hence facilitate viron fusion, with the support of p24 binding assay and direct visualization by microscope or electron microscope.

The paper further revealed that SEVI is a general enhancer of HIV-1 infection, independent of viral genotype or phenotype, and cell type.

This is a decent paper unveiling the role of semen in HIV transmission. On the other hand, instead of exposing semen directly to cells expressing CD4 / CXCR4 / CCR5, I am more curious what role does semen play in getting HIV virons breaking through vaginal mucosal cells. After all, this is the place where body fluids meet in coital acts, and true infection of T cells or dendritic cells can only happen after that.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine-Microbiology, Medicine-Immunology, Medicine-Infectious Disease, Medicine-Urology, Medicine-Biochemistry, Medicine-Urology-Prostate, Medicine-Urology-STDs, Medicine-Infectious Diseases-STDs, HIV, Human Immunodeficiency virus, Medicine-Proteometrics, Semen, Seminal fluid, HIV-1, Body fluids, Sexually Transmitted Diseases, Chromatography, CD4, CXCR4, CCR5, PAP, Prostatic acidic phosphatase, mass mass spectrometry, Thioflavin T, Congo red, X-ray powder diffration, electron microscopy, amyloid fibrils, beta sheet, SEVI, Semen-derived Enhancer of Virus Infection, p24 binding assay, vaginal mucosal barrier, Medicine, Medicine-Biomedical science, Medicine-Biological Science

GABA beyond the Nervous System!

A paper by And鄚g M et al. drew my attention, idicating that GABA (gamma-aminobutyric acid) and GABA receptors also play important roles outside the central nervous system.

Published on Nature last month, the authors showed the impact of GABA upon cell proliferation and cell cycle regulation by the following three models: (1) embryonic stem cells, (2) blastocyst cells, (3) neural crest stem cells (NCS). Starting with expression analysis of these cells for GABA receptors, in addition with electrophysiologic studies, they showed hyperpolarization of the cells upon activation of GABAA receptors by GABA agonist. Then, with pharmacological approaches, they observed that the colonies are smaller, there are fewer cells, and more cells stayed in S stage of cell cycle, when GABAA agonist is given. And it is verified by reversing the effect with GABAA antagonist. Genetically, knocking down GABAA receptor also reverses this negative proliferation effect of GABA.

Digging into the molecular level further, the authors revealed that this regulation by GABA and GABAA receptor is dependent on PIKK (phosphatidylinositol-3-OH kinase-related kinase) family of kinases, including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia Rad3-related), and DNA-PK (DNA protein kinase). It is also contigent on H2AX (Histone H2A). The authors provided evidences of both pharmacological inhibition and genetical knock-down by RNAi.

Therefore, here is the proposed model: GABA or other GABA agonist activate GABAA receptor, inducinghyperpolarization of these stem cells. Subsequently, it signals through PIKK family such as ATM/ATR/DNA-PK, and histone variant H2AX. These S-phase checkpoint kinases thus block the cell cycle at S phase, resulting in sharp decrease of cell proliferation, and an attenuation of progenies in this stem cell niche.

The findings denote a fundamentally different mechanism of proliferation control of stem cells compared to somatic cells. What impressed me more is that, although shown upstreamingly rather than other terminal-differentiated cells, GABA has her role outside the nervous system. Here we see its importance in early development of an organism.


Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: GABA, gamma-aminobutyric acid, CNS, Central Nervous System, GABA receptor, GABAA receptor, GABA-A receptor, Cl-, Chloride channel, cell proliferation, Med-Neurology, Med-Neuroscience, Developmental Biology, Med-Developmental Biology, ESC, Embryonic Stem Cell, Blastocyst, NCS, Neural Crest Stem Cells, Electrophysiological studies, patch-clamp technique, Med-Cell Biology, Med-Molecular Biology, Med-Pharmacology, Med-Genetics, siRNA, Knock-down, PIKK, phosphatidylinositol-3-OH kinase-related kinase, ATM, ataxia telangiectasia mutated, ATR, ataxia telangiectasia Rad3-related, DNA-PK, DNA protein kinase, H2AX, Histone H2A, Cell cycle, S phase, checkpoint, BrdU staining, 5-bromo-2-deoxyuridine, PI, Propidium iodide