Paper Numero Uno

Miles Murphy

Professor Macosko

1^st FYS Paper

HIV/AIDS, How to Stop It?

HIV itself is not a dangerous, but not deadly, virus. When HIV enters the bloodstream of an individual it attacks the CD4 receptor T-Cells. It uses CD4 and another co-receptor, either CCR5 or CXCR4 to bind to the cell and invade it.[1] CCR5 is a chemokine receptor. Chemokine receptors are imbedded in the cell membrane. They are generally 350 amino acids long with 7 transmembrane domains. The picture to the left is an example of the classic form of co-receptors like CCR5 and CXCR4.[2] The HIV molecule uses glycoproteins(gp) 120 and 41 to bind to those two receptors.[2] CD4 binds with gp41 and CCR5 binds with gp120.

The capsule enters the host cell and the RNA is translated into a DNA strand via reverse transcriptase, protease, and integrase and then inserted into the host cells DNA. The DNA codes for the host T-Cell to produce the RNA strand. The RNA codes for the protein shell, reverse transcriptase, integrase, and protease that are packaged along with the RNA strand as a new virus. The picture above to the right is an example of what a classic HIV cell looks like. The newly produced viral cells exit the cell and take some of the cells cytoplasm along with them gradually destroying the cell. T-Cells are an instrumental part of the immune system.[3]

When a person’s CD4 T-Cell count becomes extremely low they are said to have AIDS, or Acquired Immune Deficiency Syndrome. This is when the body’s immune system has been weakened by HIV. The body is then an easy target for many opportunistic infections such as pneumonia or tuberculosis (more common in Africa). AIDS unlike the common misconception is not a separate disease that you catch in combination with HIV. It is merely an advanced stage of the infection.

AIDS is a serious global issue. As of the end of 2007 there were an estimated 33.2 million people living with HIV/AIDS. In the year 2007 approximately 2.1 million people died as a result of HIV/AIDS. In North America there are an estimated 1.3 million people living with it. In Sub-Sahara Africa the epidemic reveals itself. There are around 22.5 million of the 33.2 million that live with HIV/AIDS in Sub-Sahara Africa. The region also accounts for 1.6 million of the 2007 HIV/AIDS deaths. These statistics also show the prevalence of diseases that are much rarer in other parts of the world. HIV/AIDS is an epidemic in Sub-Sahara Africa, but also the rest of the world. [4]

Diseases have cures. Polio caused a vaccine to be developed by Dr. Jonas Salk of the University of Pittsburgh. Tuberculosis has both vaccine prevention and antibiotic treatment. The list of diseases that are managed with either vaccine or treatments goes on and on. HIV/AIDS is one of the few wide spread diseases that has no vaccine and no totally effective treatment. There are treatments for HIV/AIDS; NRTIs (Nucleotide/Nucleoside analog reverse transcriptase inhibitors) effectively block the transcription of the RNA.

One prevention/treatment that is interesting involves the entry of HIV to CD4 T-Cells. It binds using CD4 and CCR5 or CXCR4. CCR5, shown to the right, is a chemokine receptor.[5] Chemokines are essentially proteins secreted by cells that have many different functions. Scientists are trying to develop an artificial chemokine that can bind to CCR5 and block the attachment of HIV.

However, an even more intriguing idea is centered on CCR5 rather than what attaches to it. In the human genome the normal dominant trait is CCR5. This receptor allows HIV-1 entrance to the cell. CCR5 is generally coded normally, but in many people of European decent there is another receptor present. This receptor is CCR5-Δ32, shown to the left.[5] It is not a different receptor entirely, but it is the result of a mutation of the coding sequence for CCR5. CCR5- Δ32 results from a 32-bp deletion. This deletion causes the receptor to lose shape. HIV-1 (the main form of HIV) cannot bind to CCR5-Δ32. This mutation found in many people effectively grants some immunity to HIV-1. This mutant can be heterozygous or homozygous and is largely found in white populations and not in Japanese or African populations.[3]

HIV-1 is the more prevalent strand in North America and Europe. HIV-2 is less prevalent and also less virulent. Both use CCR5 as a receptor, though HIV-2 is more varied in how it bonds. The CCR5-Δ32 presents interesting possibilities for aids prevention, treatment, and possible cure.

HIV-1, as mentioned before, uses CCR5 to gain access to the CD4 T-Cells. If this co-receptor could be altered it would be a major roadblock for HIV-1. This may be accomplished, but it is rather difficult to fathom how. With a 32bp deletion in the specific coding region for CCR5 the result is CCR5-Δ32. The problem is the method with which the mutant could be generated in everyone.

Topics such as gene therapy would be ideas that might be able to aid in solving this problem. Gene therapy is when a certain code is entered into an RNA strand which is then inserted into an individual’s cells to correct problems. In the case of the CCR5 mutant a 32bp section needs to be deleted, not added. Gene therapy may have the solution. Abnormal genes can be replaced with normal genes. In a reverse of the process CCR5 could be the abnormal gene that is replaced by the Δ32 mutant.

The problem with the CCR5- Δ32 mutant is that the mutant doesn’t provide some of the same resistance to other viruses that CCR5 provides. One virus in particular in Africa that is affected by CCR5 is the West Nile Virus. With the presence of the normal CCR5 chemokine receptor West Nile is much less fatal. CCR5 is said to restrict the viruses progress either at entry or further along in the infection. The mutant is not capable of this same restriction.[6] CCR5 and its mutant form both provide resistance to life-threatening diseases.

Another interesting method of preventing the spread, treating, or curing of HIV/AIDS is the method of blocking CCR5 for use by HIV-1. Peptide T functions as a competitor for the CCR5 bonding site. When peptide T is present with CCR5 the chemokine receptor is no longer able to bond to gp120. This bonding is instrumental for HIV-1 to enter its target cell.[7] Without the bond HIV-1 would not be able to enter CD4 T‑Cells and would effectively be stalled unless it could find another co-receptor to use for entry to its host cells.

An additional method involves another peptide. The synthetic peptide WKYMVm activates FPRL1 which is another chemokine receptor. When active this machine inactivates CCR5 and CXCR4 by means of desensitization and down grading. Peptide WKYMVm doesn’t bond to the co-receptor like peptide T. It blocks HIV-1 from using CCR5 and CXCR4 as a secondary effect to its actual action. [8]

HIV-1 is a disease that is very difficult to combat for more than one reason. Though, with increased understanding about the retrovirus it will become easier to combat. Methods of fighting the disease involving CCR5 or other receptors that HIV-1 is reliant upon are at this point much more viable than a vaccine for HIV-1. Vaccines have been produced and are continued to be worked on. However, the most difficult part of finding a means to combat HIV-1 is that the virus is highly mutable. Every HIV-1 virus is not identical. It is a difficult process to find a method that would equally disable all possible variants of HIV-1. The below picture is a graph from the PBS program, The Age of AIDS. This diagram demonstrates just how many varieties of HIV-1 there are.

With many diseases a vaccine is made of damaged or inoperable viruses. With HIV this is not as safe. The mutations it undergoes that produce the variety may allow the virus to re-establish its variety and numbers and the vaccine would become a potentially lethal injection. [9]

Samuel Beckett an Irish writer said, “Ever tried. Ever failed. No matter. Try Again. Fail again. Fail better.” These words are inspiring to scientist’s ears, especially in the case of HIV-1. HIV/AIDS is a global issue with no simple cure, yet. The constant works of countless scientists bring new and exciting ideas to combat this dreadful disease. A few years ago the idea of possibly genetically engineering populations to be immune to HIV-1 was a dream and now it’s a possibility. Who knows when a cure to HIV/AIDS may come about, but it’s close. With ideas involving the tiny machines such as CCR5 HIV/AIDS can be cut of at its legs unable to move. HIV/AIDS is a very damaging virus, but it is not unmanageable or incurable.

Works Cited

1. Majka, M., et al., Biological significance of the expression of HIV-related chemokine coreceptors (CCR5 and CXCR4) and their ligands by human hematopoietic cell lines. Leukemia, 2000. 14(10): p. 1821-32.

2. Chan, D.C., et al., Core structure of gp41 from the HIV envelope glycoprotein. Cell, 1997. 89(2): p. 263-73.

3. Murdoch, C. and A. Finn, Chemokine receptors and their role in inflammation and infectious diseases. Blood, 2000. 95(10): p. 3032-43.

4. Joint United Nations Programme on HIV/AIDS. and World Health Organization., AIDS epidemic update : December 2007. 2007, Geneva, Switzerland: UNAIDS. 60 p.

5. McNicholl, J.M., et al., Host genes and HIV: the role of the chemokine receptor gene CCR5 and its allele. Emerg Infect Dis, 1997. 3(3): p. 261-71.

6. Glass, W.G., et al., CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med, 2006. 203(1): p. 35-40.

7. Redwine, L.S., et al., Peptide T blocks GP120/CCR5 chemokine receptor-mediated chemotaxis. Clin Immunol, 1999. 93(2): p. 124-31.

8. Li, B.Q., et al., The synthetic peptide WKYMVm attenuates the function of the chemokine receptors CCR5 and CXCR4 through activation of formyl peptide receptor-like 1. Blood, 2001. 97(10): p. 2941-7.

9. Stephenson, J., In HIV vaccine efforts, new strategies and patience are needed in equal measure. Jama, 2002. 288(21): p. 2671-2.