Why AIDS?

Science News, March 27, 1999 by Damaris Christensen

Over the past 15 years, governments and institutions have poured millions of dollars into AIDS research. Researchers and doctors have dramatically improved treatments for the disease and gained new understanding of how HIV, the virus that causes AIDS, infects cells. Nevertheless, scientists still understand relatively little about how HIV causes the immune system to collapse, the ultimate consequence of infection.

Most researchers have held that HIV directly kills the immune cells called helper T cells, or CD4 cells, eventually exhausting an immune system that is frantically making replacements. The latest studies, however, suggest that different pathways of CD4 cell disruption may be more important.

Some researchers now suspect that the virus chokes off the supply of new immune cells. Still others are beginning to suggest that HIV changes the signals that send immune cells migrating through the body, directing CD4 cells away from the blood where they normally circulate and toward sites where they may be destroyed.

The disagreement is more than an academic issue. Understanding how HIV triggers immune-cell depletion may eventually enable researchers to block its devastating effects. Also, new knowledge could reveal strategies for AIDS therapies that go beyond the drugs that patients now take to slow replication of HIV.

Without knowing more about how HIV ultimately destroys the immune system, however, it is unclear whether drug treatments alone will be enough to restore a person's immune system and perhaps eventually cure the disease.

Early infection with HIV is marked by symptoms similar to mononucleosis: fever, enlarged lymph nodes, rash, muscle aches, and headaches. Within 1 to 3 weeks, the immune system gets some control over the virus by producing antibodies and cells that recognize and kill some of the infected cells.

HIV reproduces itself quickly, however, and continues to replicate throughout the course of infection. Because HIV contains RNA and uses it as a template for DNA during reproduction, the agent is classified as a retrovirus. Six months or so after infection, HIV reproduction reaches a set point, which varies from patient to patient. In this stage of disease, a person is unlikely to notice any symptoms. However, the higher the set point, the greater the amount of virus carried, and the faster a person is likely to develop AIDS.

Over the next 8 to 10 years, the virus slowly overwhelms the immune system, eventually causing a catastrophic decline in the number of CD4 cells. When the concentration of CD4 cells drops below one-quarter the normal concentration, a person is said to have AIDS. The ensuing immune deficiency renders the person vulnerable to the opportunistic infections that mark the disease, such as tuberculosis and the rare cancer known as Kaposi's sarcoma.

Exactly how HIV eludes the immune system so long and effectively is unclear. Researchers suspect that part of the virus's elusiveness lies in its tendency to infect the very cells that are activated to fight off the infection. CD4 cells, the white blood cells that HIV primarily targets, marshal responses from two other kinds of immune cells: those that produce antibodies and those that destroy infected cells directly.

Only a small proportion of a person's CD4 cells are typically dividing--posing a problem for HIV. The virus can't replicate efficiently without hitching a free ride on the protein-making machinery of a T cell that is already reproducing. However, when researchers began to measure how much virus infected people typically carry, concentrations of HIV were higher than would be expected given CD4 cells' reproduction rate.

In 1995, David D. Ho of the Aaron Diamond AIDS Research Center in New York and Alan S. Perelson of Los Alamos (N.M.) National Laboratory calculated that HIV infects and destroys several billion CD4 cells each day throughout the course of disease.

That rate of cell destruction would lead to AIDS more quickly than has been observed unless the immune system increases CD4 cell production above normal, they said. While replenishing the population, rapidly dividing CD4 cells present additional targets for the virus.

The stresses of initiating massive production of new cells in response to depletion of CD4 cells must be what eventually triggers the especially marked decline in CD4 levels, asserted Ho and Perelson. Just as an ovary can only produce so many eggs over a woman's lifetime, so can the immune system manufacture only a certain number of new cells, they reasoned.

This model accounts for several characteristics of HIV treatment, says Ho. These include the rapid drop in HIV concentration and the quick rebound in CD4 cell counts detected in blood samples after a person begins antiretroviral therapy and the rapidity with which drug-resistant viruses develop.

On the other hand, Ho's theory fails to account for the observation that CD4 cells move from tissues and lymph nodes to the blood soon after antiretroviral therapy begins. The model also assumes that the dynamics of CD4 cell turnover are similar in both early and late HIV infection, which may not be the case, according to Mike McCune of the Gladstone Institute of Virology and Immunology at the University of California, San Francisco.