HIV/AIDS: Signs, Symptoms and Gene Therapy
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The first AIDS cases were described in 1981. HIV was discovered and identified as the agent for AIDS by Luc Montagnier of France and Robert Gallo of the United States in 1983-1984, leading to some probability regarding to which the first. In the past, the virus was called Human T-Lymphotropic Virus type III (HTLV-III) or Lymphadenopathy-Associated Virus (LAV). In 1986, the genome of the virus was cloned and sequenced. The name HIV has been in use since 1986.
As of the end of 2004, there were an estimated 39.4 million people around the world living with HIV or AIDS, 25.4 million of whom were in sub-Saharan Africa.
In some parts of the United States, it is illegal for a person with HIV to knowingly infect a person with the virus. This is also the case in most Western countries.< As of the end of 2004, there were an estimated 39.4 million people around the world living with HIV or AIDS, 25.4 million of whom were in sub-Saharan Africa.
In some parts of the United States, it is illegal for a person with HIV to knowingly infect a person with the virus. This is also the case in most Western countries. (1)
HIV stands for Human Immunodeficiency Virus. A virus can only survive by living in the cells of another organism. HIV is a type of virus called a retrovirus: It incorporates itself into the genetic material of cells called 'CD4 white blood cells', which are part of the immune system. This process is called 'reverse transcription', and it enables HIV to replicate. This leads to destruction of the CD4 cells and damages the immune system.(2)
What is AIDS?
AIDS stands for Acquired Immune Deficiency Syndrome. A syndrome is a set of signs and symptoms that occur together, as a result of a specific cause. The syndrome of AIDS is caused by HIV. However a person infected with HIV may not necessarily progress to having AIDS.
HIV causes AIDS by damaging the immune system and making the body vulnerable to 'opportunistic infections'. These are called 'opportunistic' because the weakened immune system gives them the 'opportunity' to take hold. These infections can cause death in people were severely weakened immune system.
AIDS was first diagnosed in 1981. Since then HIV and AIDS have spread rapidly and cases have been reported in more than 150 countries. At the beginning of 2004 it was estimated that nearly 42,000,000 people were living with HIV and AIDS.
In Australia at the beginning of 2004, more than 20,000 people have been diagnosed with HIV infection. Over 8000 of these have been diagnosed with AIDS, and nearly 6000 people have died from AIDS related illnesses.
Types of HIV
There are two types of HIV: HIV-1 and HIV-2. Both types are transmitted by sexual contact, through blood, and from mother to child, and they appear to cause clinically indistinguishable AIDS. However, it seems that HIV-2 is less easily transmitted, and the period between initial infection and illness is longer in the case of HIV-2.
Worldwide, the predominant virus is HIV-1, and generally when people refer to HIV without specifying the type of virus they will be referring to HIV-1. The relatively uncommon HIV-2 type is concentrated in West Africa and is rarely found elsewhere
The strains of HIV-1 can be classified into three groups : the "major" group M, the "outlier" group O and the "new" group N. These three groups may represent three separate introductions of simian immunodeficiency virus into humans.
Group O appears to be restricted to west-central Africa and group N - discovered in 1998 in Cameroon - is extremely rare. More than 90% of HIV-1 infections belong to HIV-1 group M and, unless specified, the rest of this page will relate to HIV-1 group M only.
Within group M there are known to be at least nine genetically distinct subtypes (or clades) of HIV-1. These are subtypes A, B, C, D, F, G, H, J and K.(3)
SIGN AND SYMPTOMS OF HIV
Early Signs and Symptoms of HIV
Some people experience signs and symptoms of HIV (Human Immunodeficiency Virus), as soon as they become infected, while others do not. When they occur, early signs and symptoms are often mistaken for the flu or a mild viral infection. Initial signs and symptoms of HIV include:
- Enlarged lymph nodes in the neck, armpits or groin
Any symptoms from becoming infected typically resolve in one to four weeks.
As you can see, the signs and symptoms of HIV infection are similar to those for many different viral infections. The only way to know for sure if you are infected with HIV is to be tested. Many people infected with HIV do not have any signs and symptoms at all for many years.
Later Signs and Symptoms of HIV/AIDS
The Centers for Disease Control (CDC) says the following signs and symptoms may be warning signs of late-stage HIV infection:
- rapid weight loss
- dry cough
- recurring fever or profuse night sweats
- profound and unexplained fatigue
- swollen lymph glands in the armpits, groin, or neck
- diarrhea lasting more than a week
- white spots or unusual blemishes on the tongue, in the mouth, or in the throat
- red, brown, pink, or purplish blotches on or under the skin or inside the mouth, nose, or eyelids
- memory loss, depression, and other neurological disorders
HIV destroys the white blood cells that are required to fight infection. As the white cell count falls to dangerous levels, numerous infections and diseases emerge. It is at this point that a person is said to have AIDS (Acquired Immune Deficiency Syndrome).
According to the CDC, as with an initial HIV infection, you cannot rely on these signs and symptoms to establish a diagnosis of AIDS. The symptoms of AIDS are similar to the symptoms of many other illnesses. AiDS a medical diagnosis made by a healthcare professional based on specific criteria established by the CDC.(4)
Getting an HIV test is easy; understanding an HIV test is not so easy. There is many type of HIV test used to determine if a person has been infected with HIV. These tests detect different substances in the blood that are present when a person has been infected with HIV. One detects HIV proteins that circulate in the body after a person has been infected. Two others detect HIV antibodies that have been produced by the body after HIV infection has occurred. Let's look a little closer at the HIV test. (5)
Enzyme-linked immunosorbent assay (ELISA). This test is usually the first one used to detect infection with HIV. If antibodies to HIV are present (positive), the test is usually repeated to confirm the diagnosis. If ELISA is negative, other tests are not usually needed. This test has a low chance of having a false result after the first few weeks that a person is infected.
Western blot. This test is more difficult than the ELISA to perform, but it is done to confirm the results of two positive ELISA tests.
Polymerase chain reaction (PCR). This test finds either the RNA of the HIV virus or the HIV DNA in white blood cells infected with the virus. PCR testing is not done as frequently as antibody testing because it requires technical skill and expensive equipment. This test may be done in the days or weeks after exposure to the virus. Genetic material may be found even if other tests are negative for the virus. The PCR test is very useful to find a very recent infection, determine if an HIV infection is present when antibody test results were uncertain, and screen blood or organs for HIV before donation.
Indirect fluorescent antibody (IFA). This test detects HIV antibodies. Like a Western blot test, it is used to confirm the results of an ELISA. But it is more expensive than a Western blot test and not commonly used.
Testing is often done at 6 weeks, 3 months, and 6 months after exposure to find out if a person is infected with HIV. (6)
RAPID HIV test
Rapid HIV testing differs from conventional HIV testing in that it allows:
- results of the test to be ready in 5 to 30 minutes
- HIV testing, counseling, and referrals can be done in one visit
Currently there are four rapid HIV tests approved for use by the Food and Drug Administration(FDA).
OraQuick / OraQuick Advanced Rapid HIV-1/2 Antibody Test - this type of HIV testing has been approved for use with venous blood, plasma, and oral fluids for the detection of HIV-1 and HIV-2. The test consists of a small test paddle. The test area on the paddle is impregnated with HIV-1 and HIV-2 proteins. The test specimen (blood, plasma, or oral fluid) is applied to the paddle (in the case of oral fluid the paddle is swabbed in the inside of the mouth) and placed in developer solution. If the specimen contains HIV, it binds with the impregnated proteins on the HIV testing paddle causing in a red line to appear. Red lines appearing in the test area and control area of the paddle indicates a positive test. All positive tests require a confirmatory blood test. The rapid test should be read no sooner than 20 minutes and no later than 40 minutes after the sample is placed in the developing solution.
Reveal G2 HIV-1 Antibody Test - this type of rapid HIV testing has been approved for use with plasma or serum specimens. While the test only takes 3 minutes to develop, the test is more complex than the OraQuick because it requires centrifuged serum or plasma. The test consists of a cartridge with a test area. Like the OraQuick, any HIV present in the test specimen binds with the protein impregnated in the test area, causing a red dot to appear. If a red dot appears along with a red line used as a control the test is considered positive, requiring a confirmatory test.
Advantages of A Rapid HIV Testing
There are distinct advantages of rapid testing over conventional testing. They include:
- they are less costly for HIV testing agencies whose budgets are limited
- almost all people tested will get post-test counseling and their results because only one visit is necessary
- because results are delivered quicker, positive people get into medical care quicker
- by learning of infections earlier, potential exposures that would have occurred between traditional testing and receiving results is reduced
- rapid tests are easier to use
- their results that are as accurate as a traditional Elisa test (7)
Gene Therapy for HIV
Definition: Any of a number of experimental treatments in which cell genes are altered. Some gene therapies attempt to provoke new immune activity; some try to render cells resistant to infection; some involve the development of enzymes that destroy viral or cancerous genetic material within cells.
When we change in the body's cells and genes to treat disease holds great potential, but it is a first steps for research to gene therapy. It will not give us direct results it may be stay for years or perhaps decades as it takes baby steps towards progress. And although dramatic advances in treating HIV are not expected to come soon, its byproducts -- such as information about the immune system and HIV infection -- may contribute to short-term advances. Our immune system includes many parts: thymus, lymph nodes, bone marrow, etc. The cells in our body are made from cells found in bone marrow. One special cell found in bone marrow, called a stem cell (One of the human body's master cells, with the ability to grow into any one of the body's more than 200 cell types), it is sometimes called the mother of all cells. If immune system is healthy and working well, then a single stem cell could divide and populate the full range of cells in your body.
Imagine there's a gene that makes a cell resistant to HIV infection. In theory, if that gene was inserted into a stem cell, all of the offspring of that cell would carry the gene and be resistant to HIV infection, HIV destroys a person's CD4+ and other immune cells, the new cells resistant to HIV would replace them and grow. Eventually these newer cells would take over and HIV could no longer weaken the immune system. Although a person may still have HIV, it could do no harm. The HIV may just die out because there are no cells for it to infect; or, it might persist but couldn't harm the immune system to any great degree.(8)
Researchers at the University of Pennsylvania School of Medicine have reported favorable results using gene-based therapies in the fight against HIV. Gene therapy uses genetically change CD4 cells that are resistant to HIV, protecting them from the damage caused by the virus. By protecting the CD4 cells, the immune system is preserved and remains able to do its job of fighting infection. In Phase I of the gene therapy trials, the experimental drug VRX496 was given to five patients who previously demonstrated resistance to conventional HIV therapies. When they re-examined the five after nine months of therapy, four of the five showed stable or increased CD4 counts, as well as improved immune system function. In addition, a decrease in HIV viral load was observed in three of the patients. researchers will follow the five patients for up to 15 years after therapy in order to get a better picture of just how well gene therapy works. In the meantime, researchers are planning a second trial, this time using patients who have well-controlled HIV viral loads to see if the results are similar. (9)
In most cases, cells are taken from the patient's body, genetically modified, and then injected back into the patient.
HIV requires the CCR5 *protein, to attach to and infect the cell. People naturally born with an alternate form of the CCR5 gene are almost entirely immune to HIV.
(CCR5 *chemokine receptor found on monocytes and lymphocytes that serves as the receptor for HIV. Polymorphisms in the coding and non-coding regions of the CCR5 gene influence the natural history of HIV infection. CCR5 (or CCCR5) stands for the CC chemokine receptor)
The researchers hoped that T-cells, including CD4 cells, in CCR5 is removed would be immune to the virus and block viral entry and replication. They also hoped the cells would multiply to make other HIV-resistant T-cells (10).
Other ways of gene therapy by use RNA targeted against the LTR region :-
First what is a LTR region?
LTR located at ends of retrotransposons.
It contain the U3, R, and U5 regions.
LTR influences the replication cycle of the virus . (11)
In this way we use of small RNA molecules which able to effect on gene inactivation and it is good method of gene therapy. It is widely used for stop increase malignant cellular and viral genes. There is a series of inhibitory RNAs named catalytic antisense RNAs, consisting of a catalytic domain, hairpin or hammerhead ribozyme, and an antisense domain. The aim of the use it to evaluate the effect of these inhibitory RNAs on HIV replication..
To test ability of this way we use A series of expression vectors has been constructed for the intracellular synthesis of inhibitory RNAs, differing in the promoter that drives their synthesis. These inhibitory RNAs were designed to act at two possible cleavage sites in the long terminal repeat (LTR) region and the TAR domain was chosen as a target for the antisense domain. Then evaluated the effects of different inhibitory RNAs in HIV replication via changes in p24 antigen levels these is will give us two result:
Catalytic antisense RNA designed to target the LTR region of HIV-1 inhibited viral replication in an eukaryotic cell environment by more than 90%
The conventional hairpin and hammerhead ribozymes, however, failed to inhibit viral replication.
This information give us a new class of inhibitory RNAs that can be used to stop HIV replication. It the importance of the ex vivo antisense effect in the inhibition of HIV.
There is a good relation between the in vitro binding efficiency of the inhibitor RNA to the HIV-1 LTR and the inhibition of viral replication.(12)
The challenges in gene therapy
To get a good result in gene therapy there are some Reasons . The first is that all parts of the immune system must be intact in order to support the stem cells in repopulating the system. However, some researchers suspect that HIV may damage the thymus. So, at some point in a person's HIV disease the thymus may not help develop new healthy CD4+ cells. Other therapies may need to be used to improve or enhance damaged immune environments (such as the thymus or bone marrow) in order for gene therapy to be successful.
Assuming that the thymus, bone marrow and other immune environments are working well, the next challenge is finding a gene that makes a cell resistant to HIV infection. Once it has been identified, it's necessary to get that gene into a cell. Some researchers are experimenting with injecting these genes directly into muscle, called direct DNA injection. However, most researchers believe that the most effective way to get a gene into a cell is by "packaging" it into a virus. Viruses that scientists use to deliver genes, called vectors, include the Adeno-associated Virus (AAV) and maybe even crippled versions of HIV.
Getting a gene into a cell is not easy. Not only must it be passed into the cell, but it must be done without harming it. It must also get into the gene without causing disease itself (and/or without combining with another virus, like HIV, and then causing disease).
In other gene therapy experiments for HIV, researchers have removed and genetically changed stem cells. However, when the new cells were injected into the body, other immune cells detected that they had been altered and remove them. Therefore, it's not merely a matter of getting the gene into cells but doing it in a way that doesn't let the other cells target and destroy the new cells.
Once a stem cell is changed with a protective gene, and it remains functional and not targeted for destruction, the next challenge is making sure the stem cells begin dividing and working well . Of course, it's key that the new cells aren't also targeted and destroyed. While the ideal target for gene therapy may be stem cells, researchers are also looking at altering their offspring CD4+ cells. This would help rid at least one of the challenges in stem cell research.
The challenge of getting genes into cells occurs in all gene research, from HIV to cancer to genetic deficiencies.
However, there are still many fear about safety, and they must be treated be carefully
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