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Viral Replication Process
Roy Gulick, M.D.
New York University ACTU
Bellevue AIDS Program
Dr. Gulick provided an overview of protease inhibitors and their collective role as the latest class of drugs in the clinical management of HIV disease in 1996.
HIV is a retrovirus containing RNA as its hereditary material. It infects CD4 or T4 or T-helper cells and stitches its genetic materials into the genes of the host cell. Each infected CD4 cell may make about 50 to 100 fully mature and infectious viral particles. Each of these viruses is capable to fully infect another CD4 cell.
The natural history of HIV infection is characterized by the progressive decline in CD4 counts over time. A normal CD4 count is considered to be above 500 cells/mm3. When a person's CD4 count falls below 350 cells/mm3, the immune system is compromised enough to generally allow certain infections to occur, such as shingles, thrush and bacterial pneumonia. These infections are typically referred to as "outpatient" infections. When the CD4 count drops to 200 cellsl/mm3 or fewer, the Center for Disease Control and Prevention (CDC) defines this as clinical AIDS regardless of the person's symptoms. Infections typically seen in people with AIDS are Pneumocystis carinii pneumonia (PCP), toxoplasmosis, mycobacteria avium complex (MAC) and cytomegalovirus (CMV). These infections are known as "opportunistic" infections.
Until recently, doctors' assessment of the patient's stage of HIV disease was largely based on symptoms and CD4 counts. Today, we have a newer test called viral load test. This is a test where a sample of blood from an infected person can be taken and sent to the lab for analysis of the actual number of copies of viral genes or RNA in a person's blood.
Viral load test was originally developed as a research tool to assess changes in a person's HIV RNA in response to antiviral therapy. People are going to hear more about viral load changes based on log declines. A log drop means the level of viral load has decreased by 90%. Two log means a 99% decrease in viral load. And 3 log means a 99.9% decrease.
Other researchers have asked the question of whether the level of viral RNA also be predictive of how a person with HIV disease will do. Results of AIDS Clinical Trials Group study 116B/117 as well as other studies have shown good correlation between viral load and disease progression. In this study, patients with greater than 10,000 HIV RNA copies/ml had a statistically significant 54% risk of clinical progression as compared to 30% in those with less than 10,000 RNA copies/ml. Furthermore, a 50% decline in HIV RNA was associated with a 32% decrease in risk of disease progression. In general, people with low CD4 counts have high viral load and people with high CD4 counts have low viral load. However, the inverse relationship between CD4 counts and viral load does not always hold true.
Many strategies have been designed to inhibit the reproduction of HIV. Most of the currently available drugs work at the stage of viral RNA to proviral DNA conversion. These drugs interfere with the function of viral reverse transcriptase (RT) enzyme and are called RT inhibitors. Most RT inhibitors are derivatives from a chemical family and are known as nucleoside analogs; they include AZT, ddI, ddC, d4T and 3TC.
In addition to the RT enzyme, HIV requires the use of another viral enzyme called protease to complete its reproduction. Protease is essential for the maturation of viral particles. It cleaves a parental viral protein block into its various smaller components for the eventual assembly into a mature and fully infectious viral particle. Protease inhibitors are designed to prevent the cleavage of viral proteins in infected cells. Viral particles produced in the presence of protease inhibitors are non-infectious.
While preliminary clinical data have shown promise with the use of protease
inhibitors and are likely to broaden therapeutic options, doctors and patients
alike are now increasingly faced with the challenge in their selection of
antiretroviral regimen. Dr. Gulick explained that one needs to know what
to look for in a protease inhibitor. He offered the following issues for
people to consider:
Antiviral Activity:
How does the drug effect viral load? How does the drug effect CD4 counts?
How long do these effects last? How fast does resistance (decreased sensitivity)
develop? Has the drug been tried in combination with other anti-HIV medications?
Does a combination of drugs improve activity or slow down resistance?
Drug Characteristics:
What side effects does the drug cause? Does the drug interact with other
medications? Does the drug require fasting or taking with food? How is the
drug supplied? (pills, liquid, etc.) How many times a day is it taken?
Plans:
When will the drug be available? How much will it cost? Who will pay for
it? What studies are ongoing? What future studies are planned? How can I
participate? How can I find out more?
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