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| Treatments Based on Understanding the Viral Life Cycle |
Treating viruses is always difficult because viruses use the translational machinery of the host cell. Most drugs that target the virus also damage the host. Drugs that can inhibit enzymes specific to the virus are, therefore, less likely to cause side effects in the host.
Most common anti-HIV drugs block key steps in viral reproduction and uptake. Several anti-retroviral drugs work by interfering with reverse transcriptase, the key enzyme of retroviruses. These drugs, the reverse transcriptase inhibitors, act when cells first become infected. Included in this group are the nucleoside analogs, chemicals that are similar to one of the bases (adenine, cytosine, guanine, and thymine) that comprise DNA, but sufficiently different enough to block viral DNA synthesis. There are also non-nucleoside reverse transcriptase inhibitors that can bind to reverse transcriptase and, thus, block the production of viral DNA. Reverse transcriptase inhibitors have been remarkably successful in preventing the spread of HIV from an infected mother to her newborn: if a pregnant woman treated with AZT (a nucleoside analog) delivers her child by caesarian, the chances of the baby being infected can be reduced to one percent.
Protease inhibitors, another major class of drugs, act later in the life cycle of the virus by inhibiting the protease enzyme. These drugs interfere with the cleavage of the viral polypeptide into functional viral enzymes.
The evolution of HIV variants that are resistant to the more commonly used medications has become a major problem. In one study as many as thirty percent of HIV patients harbored resistant viruses. The virus mutates rapidly, and variants that are able to survive in the presence of drug - particularly when circulating levels of the drug are lower - rapidly take over the population. Patient adherence to drug regimens is critical to reducing the emergence of resistant viruses; even the timing of medication can be important. Unfortunately, given the side effects of current treatments, adherence is difficult. Protease inhibitors can cause nausea and diarrhea, and some of the nucleoside reverse transcriptase inhibitors can cause red or white blood cell levels to drop. Painful nerve damage and inflammation of the pancreas can also result.
Beginning in the mid-1990s, an increasing number of HIV-infected individuals began a drug regime called highly active antiretroviral therapy (HAART), a combination of three or more anti-HIV drugs taken at the same time. The simultaneous intake of multiple drugs, each targeting different aspects of the viral life cycle, circumvents the ability of the virus to mutate and become resistant to the drugs. Combined therapies, often called "cocktails," can knock virus back to undetectable levels and improve patient health significantly. With the advent of HAART, deaths from HIV began to decline in the U.S. in 1997. Unfortunately, HAART has several long-term side effects including kidney, liver, and pancreatic problems; and changes in fat metabolism, which result in elevated cholesterol and triglyceride levels and an increased risk for strokes and heart attacks. In addition, some viruses have evolved resistance to HAART. Given these side effects, some physicians recommend that HAART be delayed until HIV-positive patients are exhibiting clear signs of AIDS. Still, HAART is often recommended in the first few weeks after exposure to bring the initial viral load down.
The treatments described above are directed at the reduction of free virus: they work only against viruses that are actively produced. Because of the latent nature of the virus they are not cures. In addition, treatments are prolonged and may be necessary for a patient's entire life. A patient who stops treatment will typically have an increase in viral numbers.
Also under investigation are treatments that take advantage of our understanding of the process of viral infection. "Fusion" or "entry inhibitors" block the proteins involved in viral uptake, such as CCR5. Integrase inhibitors affect the enzyme necessary for the integration of viral DNA into host DNA. Both have shown promise.
Treatments Based on Understanding the Immune System
Development of novel treatments for HIV also depends on an understanding of the choreography of chemical signals that regulate immune function. Because cellular immunity is key to clearing viral infections, increasing the T cell response is critical to clearing HIV. Interleukin 2 (IL-2) is a cytokine produced by TH cells that promotes the growth of other T cells. Recombinant IL-2, which has the same activity as the native protein, has been shown to increase CD4 cell numbers in individuals in the early stages of HIV infection. Viral numbers, though, do not seem to go down with this treatment alone. However, IL-2 administered with HAART resulted in more individuals with undetectable viral loads when compared to treatment with HAART alone. One frustration with HIV treatments is the inability to affect cells that harbor provirus. IL-2 administered intermittently to patients with more advanced HIV could work to stimulate viral production and stimulate HIV specific immune responses. Such strategies are under investigation.
Other treatments under consideration target virally infected cells. Some CD8 cells seem to secrete soluble factors that suppress HIV replication. Understanding how these factors work may help define new treatments.