Biology of a Cure for HIV

“When are they going to find a cure, doc?”

HIV is epidemic, infecting 2.5 million people a year, and 33 million people worldwide and has been responsible for more than 25 million deaths. During the early days of the epidemic, many people who were infected died within a matter of months. We have crossed significant hurdles since then. Therapy for HIV started with just one drug – zidovudine, or AZT – and has evolved into combination therapy with several potent drugs. Today standard treatment for HIV is called Highly Active Anti-Retroviral Therapy, or HAART. Patients who take HAART can mitigate most of the fatal complications of HIV infection, although many people still do not have access to these life-saving medications. Despite the success of HAART, recipients are committed to lifelong therapy which can be costly, toxic, and complicated. The risk for someone who stops HAART is that the disease can come back, putting the sufferer at constant risk of a poor outcome. Understandably, many HIV-infected persons wonder why there hasn’t been a cure. Some patients have even expressed concern that there are doctors, pharmaceutical companies, and even governments who are suppressing a cure. Before such human failures are blamed for HIV, we still have the difficult challenge of HIV itself.

Some of the reasons why HIV has proven so tenacious lie deep within the biology of the virus...

Taking a fast hold…

From the earliest time points after transmission, HIV quickly insinuates itself into an unsuspecting host patient, like a parasite. HIV is primarily acquired by blood and body fluid exchange through sexual transmission (heterosexual or homosexual) or via the bloodstream directly (in the case of an improperly screened blood supply or intravenous drug use). No matter how it is acquired, once introduced into the body swarms of HIV virus particles (called virions) quickly spread to the body’s lymph nodes – the transit locations for most immune cells. HIV then multiples vigorously and from the lymph nodes disseminates widely throughout the body. Since HIV infection is not localized to one discrete area of the body, therapy, in order to be effective, must penetrate all of the nooks and crannies in which HIV may be hiding. At the current time not all of the drug constituents of HAART pervade into the various HIV-hosting compartments in the body. An example of this is HIV and the brain. Although HIV infects the brain and can lead to significant dementia, some drugs penetrate the fluid around the brain very poorly. People who take those drugs have undetectable viral quantities in routine blood tests, but may still have detectable HIV in the brain fluid, making control of the virus more challenging.

Another reason why a cure is not forthcoming is because of the concerted attack HIV poses to our immune system. The hallmark of HIV infection is the rapid, progressive loss of important cells of the body’s immune organs, the infected person’s CD4 T cells, leading to the Acquired Immunodeficiency Syndrome or, the more familiar moniker, AIDS. The CD4 T cell is critical for guiding various aspects of the body’s immune responses towards the many microbes to which we are exposed, including HIV itself. Even antibiotics require our immune system to do the majority of the work in cleaning up infections. The loss of CD4 T cells not only makes us vulnerable to opportunistic infections but also limits our ability to eradicate HIV from our system, even with HAART. The remaining immune cells are stymied by the propensity of HIV to mutate rapidly, making it challenging for consistent patterns to be recognized by the host. (At the risk of oversimplification, the immune system works by recognizing constant and variable patterns on ‘foreign’ materials and microbes that don’t originate in the host and targeting these invaders and the cells that harbor them for destruction and elimination.)

“But doesn’t HIV therapy improve the CD4 T cell counts?”

It’s true that the CD4 T cells in the blood are replenished when patients consistently take HAART. But despite the best available therapy, HIV-infected persons retain residual defects in their immune system. For instance, the majority of CD4 T cells are, in fact, found in the intestinal wall, and these are not fully replenished by HAART. Though it is difficult to predict the significance of these residual intestinal immune defects, one can envision that HIV could take advantage of holes in the immune system in order to persist in the host.

The Persistence (Despite) Time

The reduction of circulating HIV virus, or viremia, by HAART is the best predictor of a patient’s long-term outcome. A relatively common scenario is to see a patient’s quantity of virus start at more than 750,000 copies per milliliter and then rapidly drop to undetectable levels with the initiation of HAART. However, studies have shown that stopping HAART is detrimental. No matter how long the patient has been taking HAART, an interruption in therapy results in the virus recovering its numbers. Where, then, does HIV hide when people are on HAART?

In addition to the widespread dissemination of HIV early on in the infection, some HIV virions also infect a smaller population of cells and that allow the virus to remain in a latent state, not multiplying the way other virions do. In this situation, the genetic material of HIV is integrated stably in between stretches of the patient’s own DNA. This population of integrated HIV virus resting within cells is called the latent reservoir. Although the virus in the latent reservoir doesn’t harm the body (as far as we know), it is sufficiently hidden from the immune system to resist eradication. In addition, currently available antiretroviral drugs are predominantly active against multiplying virus. Because this latent state of HIV is characterized by a general lack of multiplicationfar fewer multiplying virions, the virus is safe even when patients are on HAART.

“Most cells in the body must die at some point. Why not wait for these reservoir cells to die, then allow HAART to finish off the virus?

In fact, the latent reservoir itself is a long-lasting population of cells infected with HIV. The lifespan of the latent reservoir has been estimated in years to decades, and only very few are thought to die during a person’s life. It is hypothesized that it would take 40 years or more for HIV within this reservoir to be eradicated entirely with HAART – an impractical amount of time for a cure.

“So is there any hope for a cure?”

Although some scientists feel that HIV eradication is impossible, the past 20 years has seen an explosion in new therapies for HIV, and there are newer agents in the pipeline. Never in the history of medicine have such large strides been made against a disease in such a short period. We still have much to learn about the virus, but with knowledge will come further answers as to how to better treat HIV. As a hopeful example, there are a number of people who were found to be resistant to HIV infection altogether. Through careful genetic studies, it was learned that cells from these individuals lacked a molecule on their surface called CCR5. CCR5 is normally manipulated by HIV to gain entry into host cells. So, the people who were CCR5 deficient were actually protected from HIV. Scientists used this knowledge to design drugs that block CCR5, thereby helping to control the ability of HIV to infect new cells. This class of drugs, CCR5 inhibitors, has recently been approved for the treatment of difficult to control HIV.

In 2008 we have crossed many important milestones in HIV research and treatment, some of which have been explored here. But we have many more milestones to come. Further investigation will reveal new ways to control HIV, until one day a cure will finally be in our grasp.