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Scientists study how HIV hides in body - Essay Example

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WASHINGTON - The AIDS virus has hideouts deep in the immune system that today's drugs can't reach. Now scientists finally have discovered how HIV builds one of those fortresses - and they're exploring whether a drug already used to fight a parasite in developing countries just might hold a key to break in.
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Scientists study how HIV hides in body
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Scientists learning how HIV hides out in the body By Lauran Neergaard, The Associated Press WASHINGTON - The AIDS virus has hideouts deep in the immune system that today's drugs can't reach. Now scientists finally have discovered how HIV builds one of those fortresses - and they're exploring whether a drug already used to fight a parasite in developing countries just might hold a key to break in.
Researchers have long struggled unsuccessfully to attack what they call reservoirs of dormant HIV, and the new work is in very early stages.
But University of Rochester scientists say it may be fairly straightforward to attack one of these reservoirs, blood cells called macrophages that HIV hijacks and turns into viral hideaways.
The new discovery shows the exact steps that HIV takes to do that - and found that some existing drugs, including a long-used treatment for leishmaniasis called miltefosine, can block the main step and thus cause these cells to self-destruct.
"It's a very smart virus," said lead researcher Dr. Baek Kim. "They have to have a very good fence to protect their house for a long time. ... Get rid of the fence, and now their house is gone."
Today's drugs have turned HIV from a quick death sentence into, for many, a chronic infection. Yet those drugs don't eliminate HIV because they can't reach the two known pools of cells where the virus can lie dormant, ever ready to resurface.
So-called memory T cells form one such pool. As the name implies, these are the cells that ensure if you get, say, measles as a child, you're forever immune. They live for years, even decades, making them a logical HIV hideout, and one that scientists have repeatedly sought to dismantle to no avail.
Macrophages, another type of immune cell, form the second pool. They roam the body looking for invaders like bacteria to gobble up. If they get harmed, such as becoming infected by a virus, they're supposed to commit suicide. But HIV instead keeps them alive long past their normal lifespan.
"Up to now, nobody has really thought about how to eliminate the macrophage reservoir," said Dr. Kuan-Teh Jeang, an HIV specialist at the National Institutes of Health. "The imagination now has turned toward, 'How do we eliminate reservoirs' ... The best way to address our problem is to simply kill those cells."
The Rochester team found that HIV produces a protein that turns on a particular cell-survival pathway. After a multistep process, it ultimately activates an enzyme called Akt that in turn prevents cell suicide, the researchers reported Thursday online in the journal Retrovirology.
That was good news, Kim said, because the Akt pathway is a culprit in certain cancers - meaning oncologists have been trying to target it for some time. So Kim put human HIV-infected macrophages in lab dishes and started adding drugs known to block the Akt pathway, to see if any killed the cells.
He had luck: Miltefosine and a cousin named perifosine both rapidly killed the macrophages, thus depriving HIV of this hideout.
Perifosine is currently being studied as a possible cancer drug. But miltefosine is known to be safe through its use in leishmaniasis patients. So Kim's goal is to rapidly study the already available miltefosine in animals, to see if it truly targets infected macrophages well enough to then test in HIV patients.
"The evidence they show is in fact pretty good," said NIH's Jeang, who says the next step should be a test of miltefosine in monkeys infected with SIV, the monkey version of the AIDS virus.
Synopsis
Human Immunodeficiency Virus (HIV) has been recognized as one of the most deadly pandemics ever to have plagued mankind in its entire history. In the year 2005 alone an estimated 2.8 million people world wide died due to HIV and an estimated 38.6 million people were said to be living with the virus [1].
The HIV virus belongs to the Family Retroviridae (it uses Reverse Transcriptase to convert its genomic RNA into DNA which is then integrated into the host genome) Sub Family Orthoretrovirinae Genus Lentivirus [2] [3]. The virus is made up of an envelope, a nucleocapsid, a nucleoid, and a matrix protein. The envelope ranges from spherical to pleomorphic in shape. Its genetic material consists of a single linear positive sense single stranded RNA which has been completely sequenced [4]. The viral genome codes for Gag, Pro, Pol, Env, and also Vif, Vpr, Tat, Rev, Vpu, & Nef [5] [6].
The envelope of the virus consists of a host derived lipid bilayer and virus encoded envelope glycoproteins. These glycoproteins are crucial for the virus's entry into the host cell. Two glycoproteins gp120 and its transmembrane subunit gp41 are important for host specificity as well viral entry. The gp120 interacts with the glycoprotein CD4 and members of the chemokine receptor family which are expressed on the surface of T lymphocytes, monocytes, dendritic cells and microglia cells [7]. On interaction with CD4, the gp120 undergoes a conformational change which allows gp41 to interact with the host membrane. This causes the fusion of the viral membrane with the host cell membrane thereby allowing the virus to inject its capsid containing RNA as well as other enzymes such as RT & Integrase into the host. Once in the host, the HIV is uncoated and the RT converts the viral RNA into cDNA which is then integrated into a transcriptionally active region of the host genome [8].
Once integrated into the genome, viral transcripts such as those for Tat (a transcriptional activator that is required for virus replication by transactivating the viral LTR promoter through interactions with cellular transcription factors) are produced which are then released into the cytoplasm and translated. After the viral protein translation, they are assembled into new virions in lipid rafts on cellular membranes [9]. On the other hand in T cells and fibroblast cells, they are assembled and released at the cell surface while in macrophages and dendritic cells, they assemble on the endosomal membrane and bud into multi vesicular bodies eventually fusing with the plasma membrane and are released [10].
A dominant feature of the pathogenesis of HIV is its infection of mononuclear phagocytes especially macrophages. Although the general mechanism of infection is relatively similar to that of T cells, one aspect that is peculiar about macrophage infection is the long term persistence of the infection. This occurs due to the fact that the infected macrophages lead unusually longer life spans as compared to uninfected cells. This has conferred macrophages the role of a reservoir of HIV perpetuating the infection and preventing the complete eradication of the virus. [11].
One approach to deal with this reservoir has been to inhibit the PI3K/Akt cell survival pathway. PI3K plays a crucial role in acting on a broad range of cellular functions in response to extracellular signals. A key downstream effector of PI3K is the serine-threonine kinase Akt which in response to PI3K activation, phosphorylates and regulates the activity of a number of targets including kinases, transcription factors and other regulatory molecules that are essential for survival e.g. inhibition of apoptosis inducing caspases (Figure 1).
Miltefosine, a drug approved in the treatment of breast cancer and Leishmaniasis inhibits the P13/Akt Pathway. On action of Miltefosine, PH-Akt is probably inhibited from reaching the plasma membrane by binding with Akt instead of PH which causes a drop in the PTEN levels and subsequently a reduction in the levels of downstream Akt kinase. This inducs hypersensitivity to the macrophage to extra cellular stresses where earlier it wasn't and therefore susceptible to cell death. (Figure 2) [12]
References
[1]
http://www.unaids.org/Epi2005/doc/EPIupdate2005_pdf_en/epi-update2005_en.pdf
[2]
http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.061.htm
[3]
http://www.ncbi.nlm.nih.gov/retroviruses/
[4]
http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgidb=nuccore&id=9629357
[5]
http://phene.cpmc.columbia.edu/ICTVdB/61106001.htm
[6]
http://www.ncbi.nlm.nih.gov/sites/entrezdb=genome&cmd=Retrieve&dopt=Protein%20Table&start=1&stop=9181&list_uids=12171
[7]
Wyatt R, Sodroski J, The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens, Science (1998), 1884-8.
[8]
Zheng, Y. H., Lovsin, N. and Peterlin, B. M., Newly identified host factors modulate HIV replication, Immunology Letters (2005), 225-234
[9]
D.H. Nguyen and J.E. Hildreth, Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts, Journal of Virology (2000), 3264-3272
[10]
Graa Raposo, Marilyn Moore, Donald Innes, Richtje Leijendekker, Andrew Leigh-Brown, Philippe Benaroch, Hans Geuze, Human Macrophages Accumulate HIV-1 Particles in MHC II Compartments, Traffic (2002), 718-729
[11]
Cassol E, Alfano M, Biswas P, Poli G, Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence, J Leukocyte Biology (2006), 1018-30
[12]
Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, Planelles V, Maggirwar SB, Dewhurst S, Kim B., Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy, Retrovirology, (2008) [Epub ahead of print]
Figure 1:
Cancer Treatment Research 2003; 115:145-67
Figure 2:
Retrovirology 2008, 5:11 Read More
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