|MadSci Network: Immunology|
1)HIV has to first induced to the receptor(protein), how could this be possible to remove the receptor without harming the cell? 2)Why HIV only attack the CD4Tcells, but not others, what factor is driving the HIV to attack and why they have to reproduce eventhough they will stay alive forever 3)can we invent some drug that harden the infected cell wall to prevent the lysis?
It is my aspiration to broadly cover some relevant topics and to thereby satiate your well-placed interest.
I will start with the basics of HIV replication so that I am assured that we can begin on the same page.
The stages of HIV replication are as follows: 1) HIV enters a CD4+ cell. 2) HIV is a retrovirus, meaning that its genetic information is stored on a single-stranded RNA instead of double-stranded DNA found in most organisms. To replicate, HIV uses an enzyme known as reverse transcriptase to convert its RNA into DNA. 3) HIV DNA enters the nucleus of the CD4+ cell and inserts itself into the cell's DNA. HIV DNA then instructs the cell to make many copies of the original virus. 4) New virus particles are assembled and leave the cell, ready to infect other CD4+ cells.
Today’s antiretroviral agents for HIV include Non-nucleoside reverse transcriptase inhibitors (NNRTIs), and Nucleoside analogues, both which work around reverse transcriptase. And Protease inhibitors that work in the last stage of the virus reproduction cycle – preventing HIV final assembly and release.
HIV’s ability to survive and thrive depends entirely on its ability to penetrate and the mechanism of a human cell. Your question seems to take issue over how HIV enters the immune cell itself. Once the HIV virion is in the bloodsteam, its gp120 glycoproteins bind to the CD4 receptor on target cells, [CD4 receptors are highest on T-helper lymphocytes (aka CD4 + T-helper cells), and to a lesser extent, macrophages, monocytes, and central nervous system dendritic cells]. Following HIV binding to the CD4 receptor, the viral envelope fuses with the infected host cell, allowing the capsid entry. Once inside, replication proceeds as previously mentioned.
So can we vaccinate, and thereby block gp120's affinity for CD4 receptor binding among target cells?
Part of the reason those vaccines against HIV, (and the common cold), are so ineffective is due in part to the viral genomes heterogeneity: It has the ability to change its genome in a critical area, in particular the gp 120 part of the “env” gene. Within it are hypervariable regions, where point mutations occur – Duplications, deletions… all that occur in multiples of 3 to preserve the codon-reading frame! This unique strategy protects the virus from the human immune system and vaccine-induced antibodies.
Despite the estimate that the rate of viral replication is over 10 billion particles a day, our human cell membranes put up a formidable defense of two sheets of densely packed, electrically charged, hydrophilic chemicals that sandwich a hydrophobic lipid layer. Carbohydrate chains projecting out and a film of tightly bound water surrounding the cell further shield this bilayer construction. All this helps keep the HIV virus away from contacting the cell membrane and docking with the CD4 protein.
To understand further the ability of HIV to penetrate a cell, we have to understand the concept of fusion.
HIV has spikes emanating from its envelope coat. These spikes have two parts: The outermost glycoprotein 120 (gp120) portion which are attached to a bundle of protein chains tightly bound together called gp41 – which imbeds in the virus at the other end.
Fusion begins with the gp 120 binding to the CD4 protein of the T cell. Once anchored, HIV attaches again to a coreceptor on the cell, generally either CCR5 or CXCR4. This double attachment releases gp41 and permits it to unfold like a jackknife. Once extended, gp 41 of the virus harpoons its newly freed end into the cell's membrane. Inserted now, gp41 once again folds back on itself creating tension, and then comes back together to hold itself tightly into place.
The gp41 chain has some interesting properties that compel it to continue folding, recoiling, harpooning and drawing the virus closer to the human T cell until its ultimate fusion. The aggregation resulting from contact, and the subsequent fusion, is like two bubbles meeting and merging to form a single larger bubble. As this happens, the virus spits its contents into the cell, thereby subverting human genetic machinery and initiating viral replication.
So how can we block the harpooning action of the viral glycoproteins? Understand this first: It is well established that for HIV to infect a cell it must attach to the CD4 molecule on the surface of the cell AND it must bind to one of two co-receptors: CXCR4 or CCR5. One idea is to stick some stuff in there to jam up the gp 41 prongs. For example, the synthesis of a peptide that can effectively block the conformational changes of the gp 41 protein might be enough to muddy up the works.
Thomas Matthews, MD, of Duke University stumbled across one such capable peptide when he created a chain of 36 amino acids that could somehow prevent HIV from infecting human cells and also prevent the cell-to-cell infection that often occurs in HIV disease; [There is a phenomenon that occurs when the gp 120 in the infects cells binds to other CD4 T-helper cells, resulting in cell-to-cell fusion. One infected cell can fuse with as many as 500 uninfected CD4+ T-helper cells, forming multinucleated giant cells].
In time it was discovered that this 36 amino acid peptide chain, (called DP178 at that time), had a great affinity for a certain part of gp41. Once attached there, it prevented gp41 from refolding back on itself. An interruption in this coiling/recoiling process can keep the HIV viron from getting close enough to the human cell membrane for fusion to occur. Neat stuff – But this was only in a test tube.
Trimeris, Inc., a pharmaceutical company, acquired the compound and named it “T-20” or “pentafuside”. Being a large peptide, the stomach would break it down, so studies were conducted using the IV route of administration. Trial one lasted 14 days and involved 16 patients. The doses ranged from 3 to 100 mg twice a day. In the four patients receiving the 100 mg dose, viral load declined below 500 copies, (as measured by an dDNA assay). A more sensitive assay measured down to 40 copies – and no significant side effects were noted.
A second trial with more patients over a longer time using up to 200 mg a day subcutaneously demonstrated an average maximum drop in viral load from 0.3 to 1.6 logs, (TR1003).
Many patients had a viralogical rebound, and the question of resistance has still not been fully elucidated. The Journal of Virology, 1998, 72:2 p. 986, indicated that two mutations of gp41, (at residues 36 and 38), is all that is required for viral resistance to the drug. Thus a question of drug resistance and reduced sensitivity remains. Taking into account the viral breakthroughs, it may be advantageous to not use TR1003 as a monotherapy, rather to use it in conjunction with other antiretrovirals.
Currently, Trimeris is doing follow up studies to evaluate possible long- term drug toxicity. Currently pentafuside is unique in that it is the only drug to “prevent” infection of the target cell. It does this by performing its job outside the cell, whereas the aforementioned antiretroviral medications require entry into the cell to perform their inhibition. In theory, this approach should work against a wide variety of viruses, even those viruses that have become resistant to existing therapies. Moreover, pentafuside may have fewer side effects because it works outside the cell.
One of the problems with pentafuside however, is that it is a large and hydrophobic molecule – Making it hard to penetrate several critical compartments of HIV replication such as the genital tract and nervous system. Douglas D. Richman, MD, of the University of California San Diego commented in Nature Medicine, 4:11, p. 1232, “a smaller molecule with more desirable phamacologic characteristics (oral bioavailability and central nervous system penetration)” might be able to be designed. Now that the target and its mechanism have come into better focus perhaps new and better drugs are on their way.
Currently I believe that the Investigational New Drug application with the U.S. FDA has allowed the initiation of phase trials of Trimeris second fusion inhibitor drug T-1249. This may be active against pentafuside- resistant virus strains.
In final note: There will probably never be a panacea in the treatment of chronic illness, whether it is diabetes, aging or HIV. It takes rather a plethora of strategies to contain disease progression. To date, we can completely contain disease progression for life in HIV infected individuals, but the financial cost and effort is incomprehensible. To completely eradicate the disease, I would suggest that the patient undergo the myriad of known successful strategies – But add to it the novel immunotherapeutic application of Th1 cellular immunity stimulants.
Jonas Salk, who developed the first vaccine against polio, died of heart failure in 1995 at the age of 80. “Salk was ahead of the times,” said one mourner in a “Science” article about Salk’s death. “While other people were looking at just the outer envelope of the virus in order to produce vaccines, he got people to thinking about looking at the whole virus and all its proteins.”
In his last years, Salk’s work centered around developing an AIDS treatment. His efforts resulted in an immune-reconstruction therapy called Remune. Early studies of the drug showed that when combined with antiretroviral therapies, Remune enhances the immune system, eliminates HIV-infected cells, and reduces the level of HIV in the blood. Rumune, whose phase III clinical trails were approved in 1996, has shown to improve immune system cytokine profiles, and enhance the immune system’s ability to recognize HIV proteins and kill cells infected with the virus.
A good therapy could be to combine Remune with antiviral drugs, and TH1 (anti-TH2) stimulatory cytokines: IL-12 and and anti-IL-4. The future of managed care for HIV seems to be multifaceted; include antivirals; augment lean body mass; enhance indigenous immune function; and, cost a lot of money!
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