HIV Research In an Age of Antiviral Therapy


By Jason Socrates Bardi

Sometimes you see them in the most public of places—huge billboards, placards on the sides of city busses, and special advertising sections in The New York Times Magazine—glossy ads with attractive models touting the wonders of the latest antiretroviral treatment combination for those with human immunodeficiency virus (HIV).

The images are sometimes subtle: a family at a graduation; a young man kickboxing or swimming; a woman with a bright smile riding a bike. The message, however, is clear: Acquired Immune Deficiency Syndrome (AIDS) is a treatable disease. With drugs, life can be extended.

Perhaps that message is too clear.

The Food and Drug Administration warned drug manufacturers last week to not go too far with their advertising claims, noting that many of these ads “do not adequately convey that these drugs neither cure HIV infection nor reduce its transmission.”

Transmission rates of HIV have increased since the advent of the type of therapy described in those ads, especially among the 15- to 25-year-old age cohort. This increase is largely due to increased high-risk behaviors—unprotected sex and intravenous drug use—among kids who may have absorbed the message that living with the virus isn’t so bad anymore.

No current treatment has ever shown efficacy at eradicating the disease from a patient. Nor do the treatments eliminate the risk of passing the virus along through sexual contact or sharing needles. HIV is a hard infection to control.

The goals of current AIDS research are still the same: finding ways to stop the spread of the virus and enable infected individuals to live longer.

"In 99.9 percent of infected individuals," says Immunology Professor Donald Mosier, "the immune response ultimately fails."

Mosier’s laboratory has an elegant model that they have developed to study HIV infection in vivo. Using this model, they can test isolates from patients at various stages in the disease and look at how the replication and infectivity of the virus alters with mutations to its genome.

They can also use the model to study basic viral dynamics and to test the efficacy of vaccine and therapeutics candidates to protect live human cells against HIV. And equally important, they can use these models to study the basic biology of HIV and its viral dynamics.

Viral Dynamics and Immune Failure

During the first stages of an HIV infection, the virus multiplies rapidly in a person’s lymphoid organs causing a burst of high concentration in the bloodstream that is known as the initial viremia. This viral burst makes a person sick and causes an immune response as CD4+ T helper cells, which are the primary target of HIV, respond to the infection. These activated CD4+ T cells stimulate B cells to produce antibodies that are specific to HIV envelope proteins, which appear in the bloodstream a few months after initial infection and are maintained at a certain level in the bloodstream throughout infection.

There is also an adaptive immune response mediated by HIV-specific cytotoxic T lymphocytes (CTL) CD8+ T cells, which learn to recognize HIV infected CD4+ T cells. These HIV-specific CTLs come along and kill infected cells by blasting them with perforin, an enzyme that pokes holes in infected cells.

The CTLs also produce a molecule, interleukin–2, which activates the differentiation of na•ve cells into HIV-specific CTLs. The levels of HIV-specific CTLs in the bloodstream increases dramatically in the first few months of infection and are maintained at high, steady numbers throughout most of the infection.

Once this CTL-mediated immune response is fully on, the immune cells continue to target and kill HIV infected cells in the body, and a leveling off occurs where the CD4+ T-helper cells stop declining and hold steady at a blood concentration slightly lower than normal. The amount of virus in the bloodstream declines and evens out as well—at the level referred to as the set point, which is a good correlate with eventual disease prognosis.

As the disease progresses, the levels of virus, antibody, CTL, and T helper cells remain more or less the same for anywhere from one to ten years or more. Clinically, this is referred to as the asymptomatic period, and throughout this entire period, the immune system is able to respond to challenges of infection and continuously kill cells infected with HIV.

Eventually, though, the immune system loses its battle with HIV, largely due to a failure of CTLs to eradicate the virus. The CTLs ultimately fail, which leads to increased killing of T helper cells.

"Even though there is—at one time—a vigorous response, it is not sustained and effective," says Mosier. "The target somehow induces that CTL to die."

Functioning normally, the CTLs should kill infected target cells repeatedly, but in HIV, they are killed in the act of killing, and this back killing has a dire effect on the immune system. "Most virus-infected cells can't fight back, but HIV-1 infected cells can."

Exactly how this occurs is one of the basic questions that Mosier has been asking, but regardless of the mechanism, the effect is clear.

"It’s not like the CTLs are not responding to the HIV infection," says Mosier, "but the longer it goes on, the less effective the response becomes."

The back killing acts as a selection in which those CTLs that are the most potent are also the ones that are the most fragile. The result for the immune system is that overall, the HIV-specific CTLs become less effective at killing the virus throughout the course of the infection.

Evidence for this can be seen under a microscope. CTLs are normally loaded with perforin granules, which they use to kill cells, but in chronic HIV patients the HIV-specific CTLs have no perforin granules.

"They are functionally neutered," says Mosier. "All the killers are killed."

Meanwhile the HIV-specific CTLs are nevertheless getting stimulated constantly. Evidence for this can be seen in the appearance of CD28+ markers on the cells, says Mosier, which only appear after long-term stimulation and are not present during primary infection. The CTLs undergo very rapid turnover during a primary HIV infection, which is evidenced by the telomere shortening—the fraying of the ends of cell chromosomes which happens each time a cell divides.

"The whole CTL mechanism gets exhausted," says Mosier.

And late in the infection, the CTLs fade away, the T helper cells decline, and the viral levels in the bloodstream shoot up once again.


Next Page | A New Hope

1 | 2 |



Immunology Professor Donald Mosier studies the dynamics of HIV in vivo.

















“It's not like the CTLs are not responding to the HIV infection, but the longer [the infection] goes on, the less effective the response becomes.”

Donald Mosier