The Agent

HIV (Human Immunodeficiency Virus) causes the disease known as AIDS (Acquired Immune Deficiency Syndrome). HIV infects cells that are critical to the human immune system and destroys their ability to fight infections. Therefore, people who have developed AIDS are unable to fight off infections by other viruses or bacteria that normally do not cause disease in healthy individuals. As a result, AIDS patients can die from infections that are normally harmless. Some AIDS patients also develop unusual cancers because of defects in their immune systems.
Source: UNAIDS
Worldwide AIDS Epidemic Statistics Summary
33.2 million people living with HIV in 2007
2.5 million people newly infected with HIV in 2007
2.1 million deaths from AIDS in 2007
HIV was first recognized as the agent that causes AIDS in 1983. In about 25 years, from the time when small, unusual clusters of infection were first noted primarily in homosexual men, approximately a million Americans have become infected with HIV. The epidemic now afflicts both males and females and all ethnic groups. About a quarter of those infected may be unaware that they are infected. The epidemic is growing most rapidly among minority populations and women. Worldwide, the picture is even more grim with over 20 million deaths from AIDS (see statistics in side box), and the epidemic is continuing to spread into new geographic regions, particularly in Asia. There is finally, however, a glimmer of hope - a new report by the United Nations AIDS program has found that, for the first time in 25 years, the incidence of new infections has stabilized. In about 10 countries, there has even been a decline in the number of new HIV infections, but the number of new infections in Eastern Europe and Asia continues to increase.
From the time a person becomes infected with HIV, there is usually a substantial lag time, generally about a decade, before an infected person develops the symptoms of AIDS (although this is highly variable from person to person and can be delayed by the use of anti-HIV drugs). Shortly after infection, individuals may experience flu-like symptoms, but then can go for many years without detectable symptoms. However, during this phase the virus continues to replicate within their bodies and can be transmitted to other people through direct contact with body fluids such as blood or semen. During this time there is usually also a slow but steady depletion of the immune system cells known as CD4 positive (CD4+) T cells that are infected by HIV. A normal person has about 1000 CD4+ T cells in a milliliter of blood. Once CD4+ T cell numbers fall to 200 cells per milliliter, the patient enters the phase of HIV infection that is known as AIDS, and it becomes increasingly difficult for these AIDS patients to fight off infections.

Courtesy: CDC/Dr. Edwin P. Ewing, Jr.
HIV belongs to a class of viruses known as retroviruses. Retroviruses use RNA to encode their genetic information rather than DNA, as human cells do. What distinguishes retroviruses from other classes of viruses is that during their replication cycle inside cells, they use a special enzyme called reverse transcriptase to convert the RNA into DNA.
Like all viruses, HIV must enter into a cell before it can replicate or make more copies of itself. There are a defined number of steps that the virus goes through to make more copies of itself. These steps require the action not only of virus proteins but also proteins within the cell that the virus “hijacks” for its own purposes.
To begin an infection, the HIV particle must encounter and bind to the CD4 receptor that is present on the surface of a subset of T cells (and also some other immune system cells called macrophages, but not on most other cells in the body). The interaction between HIV and the CD4 molecule, along with another molecule called a co-receptor, allows HIV to enter the cell.
The virus enzyme reverse transcriptase then converts the RNA to DNA.
Another viral enzyme called integrase inserts the virus’ DNA into the cell’s DNA in a step known as integration.
Next, the cellular machinery, with the help of virus protein named Tat, makes many RNA copies of the virus in a process called transcription.
The RNA copies are then used to make virus proteins, and the RNA copies and virus proteins are assembled into new virus particles.
The long chains of virus proteins in the virus particle have to be cut into smaller pieces by another viral enzyme called protease. The new HIV particles are released from the cell by a process called budding and then can go on to repeat the cycle and infect more and more CD4+ T cells.

Important steps in the replication of HIV are blocked by anti-HIV drugs.
Scientists have spent many years trying to understand the details of these steps, because these steps represent possible targets for drug intervention. Because each of these steps is required for the virus to produce more copies of itself, blocking these steps should prevent the virus from continuing to replicate. Until recently, anti-HIV drugs were available that block three different steps in the HIV replication cycle - the entry of the virus into the cell, the reverse transcription step that converts RNA to DNA, and the protease step which is needed to produce the right forms of the virus proteins (see diagram). In the fall of 2007, a drug that blocks another step in the virus replication cycle was approved. The new drug inhibits the integrase enzyme that is necessary for the virus to insert itself into the host cell genome. It is most effective to use a combination of drugs that blocks multiple steps in the HIV replication cycle, a treatment regimen called HAART (highly active antiretroviral therapy).