Wednesday, 26 August 2020

AIDS : HIV virus invasion & Future treatment of HIV



A divers array of viruses occur among animal. A good way to gain a general idea of what they are like is to look at one animal virus in detail. Here we look at the virus responsible for a comparatively new and total viral disease. Acquired immuno-deficiency syndrome (AIDS). AIDS was first reported in the United States in 1981. It was not long before the infections agent, human immunodeficiency virus (HIV), was identified by laboratories in France and United States. Study of HIV revealed it to be closely related to a chimpanzee virus, suggesting that it might have been introduced to humans in central Africa from chimpanzees. Infected individuals have little resistance to infection, and nearly all of them eventually die of diseases that non-infected individuals easily ward off. Few who contract AIDS survive more than a few years untreated.

The risk of HIV transmission from an infected individual to a healthy one in the cause of day to day contact is essentially non existent. However, the transfer of body fluids, such as blood, semen, or vaginal fluid, or the use of nonsterile needles, between infected and healthy individuals poses a severe risk.

The incidence of AIDS is growing very rapidly in the United States. Over one million people were estimated to have been infected by HIV by the mid 1990s. Many perhaps all of them will eventually come down with AIDS. AIDS incidence is already very high in many African countries.

How HIV Compromises the Immune System

In normal individuals, an army of specialised cells patrots the blood stream, attacking and destroying any invading bacteria or viruses. In AIDS patients, this army of defenders is vanquished. One special kind of white blood cell, called a CD4+ T cell is required to cause the defending cells to action. In AIDS patients the virus homes in on CD4+ T cells, infecting and killing them until none are left. Without these crucial immune system cells, the body cannot mount a defense against invading bacteria or viruses. AIDS patients die of infections that a healthy person could fight off.

Clinical symptoms typically do not begin to develop until after a long latency period generally, 8 to 10 years after the initial inflation with HIV. During this long interval, carriers of HIV have no clinical symptoms but are apparently fully infectious, which makes the spread of HIV very difficult to control. The reason for the long latency period puzled researchers for some times. In some viral infections, such as Herpes, the DNA inserts itself into the host cells. Chromosome as a provirus, much as a bacteriophage does, where it remains inactive until some future event causes it to be removed from the chromosome and resume activity. This does not appear to be the case with HIV. Evidence indicates that the HIV infection cycle continues throughout the latent period, the immune system suppressing the ongoing infection. Eventually, however, a random mutational event in the virus allows it to quickly overcome the immune defense.

The HIV Infection Cycle

The way HIV infects humans provides a good example of how animal viruses replicate. Most other viral infections follow a similar course, although the details of entry and replication differ in individual cases.


When HIV is introduced into the human blood stream, the virus particle circulates throughout the entire body but will only infect CD4+ T-cells. Most other animal viruses are similarly narrow in their requirements. Polio goes only to certain spinal nerves, hepatities to the liver, and rabies to the brain. How does a virus such as HIV recognize a specific kind of Larget cell? Every kind of cell in the human body has specific array of cell surface glycoprotein markers at serve to identify them to other similar cells. Each HIV particle possesses a glycoprotein at precisely fits a cell surface marker protein called on its surface are infected CD4 on the surface of immune system cells called macrophages and T-cells. Macrophages are infected cells.

Entry into Macrophages

After docking onto the CD4 receptor of a macrophage, HIV requires a second macrophage receptor, called CCR5, to pull itself across the cell membrane. After gp 120 binds to CD4, it goes through conformational change that allows it to bind to CCRS. Investigators speculate that after the conformational change, the second receptor passes the gp 120-CD4 complex through the cell membrane, triggering passage of the contents of the HIV virus into the cell by endocytosis, with the cell membrane bolding inward to form a deep cavity around the virus.


Once inside the macrophage, the HIV particle sheds its protective coat. This leaves virus RNA floating in the cytoplasm, along with a virus enzyme that was also within the virus shell. This enzyme, called reverse transcriptase, synthesizes a double strand of DNA complementary to the virus RNA, often making mistakes and so creating new mutations. This double- stranded DNA directs the host cell machinery to produce many copies of the virus. HIV does not rupture and kill the macrophage cells it infects. Instead the new viruses are released from the cell by exocytosis. HIV synthesizes large numbers of viruses in this way, challenging the immune system over a period of years.

Entry into T Cells

During this time, HIV is constantly replicating and mutating. Eventually, by chance, HIV alters the gene for gp 120 in a way that causes the gp120 protein to change it's second receptor allegiance. This new form of gp 120 protein prefers to bind instead to a different second receptor, CXCR4, a receptor that occurs on the surface of T- lymphocyte CD4+ cells. Soon the body's T-lymphocytes become infected with HIV. This has deadly consequences, as new viruses exist the cell by rupturing the cell membrane, effectively killing the infected T-cell. Thus, the shift to the CXCR4 second receptor is followed swiftly by a steep drop in the number of T-cells. This destruction of the body's T-cell blocks the immune response and leads directly to the onset of AIDS, with cancers and opportunistic infections free to invade the defenseless body.

The Future of HIV Treatment

New discoveries of how HIV works continue to fuel research on devising ways to counter HIV. For example, scientists are testing drugs and vaccines that act on HIV receptors, researching the possibility of blocking CCR5, and looking for defects in the structures of HIV receptors in  individuals that are infected with HIV but have not developed AIDS.

Combination Drug Therapy
A variety of drugs inhibit HIV in the test tube. These include AZT and its analogs (which inhibit virus nucleic acid replication) and protease inhibitors (which inhibit the cleavage of the large polyproteins encoded by gag, poll, and env genes into functional capsid, enzyme, and envelope segments).

When combinations of these drugs were administered to people with HIV in controlled studies, their condi- tion improved. A combination of a protease inhibitor and two AZT analog drugs entirely eliminated the HIV virus from many of the patients' bloodstreams. Importantly, all of these patients began to receive the drug therapy within three months of contracting the virus, before their bodies had an opportunity to develop tolerance to any one of them.Widespread use of this combination therapy has cut the US AIDS death rate by three-fourths since its introduction in the mid-1990s, from 43,000 AIDS deaths in 1995 to 31,000 in 1996, and just over 10,000 in 1999.
Unfortunately, this sort of combination therapy does not appear to actually succeed in eliminating HIV from the body. While the virus disappears from the blood- stream, traces of it can still be detected in lymph tissue ol the patients. When combination therapy is discontinued, virus levels in the bloodstream once again rise. Because of demanding therapy schedules and many side efects, long-term combination therapy does not seem a proms ing approach.

Using a defective HIV Gene to Develop Vaccines and Drug therapy
Recently, five people in Australia who are HIV- positive but have not developed AIDS in 14 years were found to have all received a blood transfusion from the samc HIV-positive person, who also has not developed AIDS. This led scientists to believe that the strain of virus transmitted to these people has some sort of genetic defect that prevents it from effectively disabling the human immune system. In subsequent research, a defect was found in one of the nine genes present in the AIDS virus.
This Gene is called nef, named for "negative factor", and the defective version of nef in the six Australians seems to be missing some pieces. Viruses with the defective gene may not be able to reproduce as much, allowing the immune system to keep the virus in check.
This finding has exciting implications for developing a vaccine against AIDS. Before this
Scientists have been  unsuccessful in trying to produce a harmless strain of AIDS that can elicit effective immune response. The Australian strain with the defective nef gene has the potential to be used in a vaccine that would use the immune system against this and other strains of HIV.

Another potential application of this discovery is its use in developing drugs that inhibit HIV proteins that speed virus replication. It seems that the protein produced from the nef gene is one of these critical HIV proteins, Because viruses with defective forms of nef donot reproduce as scen in the cases of the six Australians. Research is currently underway to develop a drug that targets the nef Protein.


In the laboratory, chemicals called chemokines appear to inhibit HIV infection by binding to and blocking the CCRS and CXCR4 coreceptors. As one might expect, people long infected with the HIV virus who have not developed the disease prove to have high levels of chemokines in their blood.

The search for HIV inhibiting chemokies is intense. Not all results are promising. Rescarchers report that in tests, the levels of chemokines were not different between patients in which the discase was not progressing and those in which it was rapidly progressing. More promising, levels of another factor called CAF (CD8+ cell antiviral factor) are different between these two groups.
Researchers have not yet succeeded in isolating CAF, which seems not to block receptors that HIV uses to gain entry to cell, but, instead, to prevent replication of the virus once it has infected the cells. Research continues on the use of chemokines in treatments for HIV infection, either increasing the amount of chemokines or disabling the CCR5 receptor. However, promising research on CAF suggests that it may be an even better target for treatment and prevention of AIDS.

One problem with using chemokines as drugs is that they are also involved in the inflammatory response of the immune system. The function of chemokines is to attract white blood cells to arcas of infection. Chemokines work beautifully in small amounts and in local areas, but chemokines in mass numbers can cause an inflammatory response that is worse than the original infection. Injections of chemokines may hinder the immune system's ability to respond to local chemokines, or they may even trigger an out of control inflammatory response. Thus, scientists caution that injection of chemokines could make patients more susceptible to infections and they continue to research other methods of using chemokines to treat AIDS.

Scientists have found that a mutation in the gene that codes for the second receptor CCR5, consisting of a 32-base-pair deletion appears to block or inhibit HIV infection. Individuals homozygons for the mutated gene allele who have been exposed to HIV or are at high risk of HIV infection have not developed AIDS. Furthermore, individuals heterozygous for the mutated allele may have some protection and may develop the disease more slowly. In one study of 1955 people, scientist found no individuals who were infected and homozygous for the mutated allele. The allele seems to be more common in Caucasian populations (10% to 11%) than in African-American populations (2%) and absent in African and Asian populations.

Treatment for AIDS involving disruption of CCR5 looks promising, as research indicates that people live perfectly well without CCR5. Attempts to block or disable CCR5 are being sought in numerous laboratories.
A cure for AIDS is not yet in hand, but many new approaches look promising.


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