Studies Show Dynamic Struggle Between Immune System, HIV

NEW YORK--Two new studies show that the human immunodeficiencyvirus (HIV) wages a constant, near steady-state battle with theimmune system--from the onset of infection throughout the courseof the disease.

The immune system destroys billions of virus particles (virions)and infected CD4 lymphocytes every day, and produces up to 1 billionnew CD4 lymphocytes daily, but so long as a few virus progenysurvive to continue replication and transmission, the virus willultimately win the struggle. A few more CD4 lymphocytes are killedeach day than are replaced, causing CD4 counts to decline graduallyin infected patients.

Rather than a static picture of how much virus is present in thebody at any one point in time, the two studies reveal the ongoingday-to-day dynamics of the infection. They show that HIV pathologyis not the product of a constant high level of virus, or of apoor immune system response, but rather the result of a dynamicprocess consisting of continuous rounds of new infection, replication,and turnover.

In both studies, one headed by Dr. David Ho, Aaron Diamond AIDSResearch Center, New York, and the other by Dr. George M. Shaw,University of Alabama, Birmingham, HIV-infected patients withbelow normal CD4 counts were given potent experimental drugs (aprotease inhibitor or a reverse transcriptase blocker) capableof blocking the virus' ability to infect CD4 lymphocytes.

The anti-HIV drugs acted quickly, destroying 99% of the HIV populationin the body, but the surviving 1% of the virus population rapidlyreestablished itself, and within 2 weeks, almost all of the newviruses were drug resistant.

Measurements of CD4 lymphocytes found that the immune system continuedworking full steam during the time of virus inhibition, producingup to 2 billion CD4 lymphocytes a day and leading to sometimesdramatic increases in patients' CD4 counts. Both reports appearin the January 12 issue of Nature (373:117-122, 123-126, 1995).

Dr. Ho, in his report, noted that during pretreatment steady statewhen CD4 lymphocyte production and destruction were balanced,the entire population of peripheral blood CD4 lymphocytes wasturning over every 15 days.

Thus, CD4 lymphocyte depletion is primarily a consequence of theirdestruction by HIV, not a lack of their production. In other words,the immune system continues to function at a high level duringthe long process of HIV infection.

Treatment Implications

This finding suggests that AIDS research should focus on therapiesthat attack the virus, rather than attempt to restore the immunesystem. Even a small reduction in viral load (free virus particlesand HIV-producing cells) might allow the immune system to maintainadequate CD4 counts.

Dr. Ho stressed that, based on these findings, AIDS treatmentmust be started as early in the infection as possible, "perhapseven during seroconversion." Further, he said, protocolsfor monitoring the efficacy of new AIDS drugs must focus on thefirst few days following drug initiation.

Dr. Shaw believes that if effective antiretroviral therapies canbe developed, they might be able to work at any stage, allowing"successful immunological reconstitution even in late-stagedisease if effective control of viral replication can be sustained."