AIDS researchers renew focus on immune system’s role in fighting HIV
Studies address structured treatment interruption
HIV/AIDS researchers are renewing their efforts to find a way to help the human body’s immune system suppress the virus over the course of a person’s lifetime. Before the advent of protease inhibitors and other highly active anti retroviral therapies (HAART), immune treatments failed because viral loads were high, enabling virus to easily overcome immune cells. Now there’s hope, as highlighted by research presented at the 7th Conference on Retroviruses and Opportunistic Infections, held Jan. 30 - Feb. 2, 2000, in San Francisco.
"I think the optimistic hope for HIV is that you’ll be able to induce an immune response that will keep the virus in check," says Bruce Walker, MD, professor of medicine at Harvard University and the director of Partners AIDS Research Center at Massachusetts General Hospital in Boston. Walker’s research group presented immune system research done by a team at Massachusetts General at the San Francisco conference.
"It’s very clear with other viruses, like all of the herpes group viruses, that people are infected with those for their entire life, but after an initial acute disease, they don’t have ongoing problems because the immune system keeps things in check," Walker explains. "And that’s what our hope is for HIV infection."
The implications of immune research are that if a successful immune treatment is found, then some HIV patients may be able to stop taking their antiretroviral drugs and still maintain a fully suppressed viral load.
"The best model we have for that are several individuals we’ve identified who are long-term nonprogressors," says Eric S. Rosenberg, MD, an instructor of medicine at Massachusetts General and Harvard Medical School in Boston. Rosenberg, who was one of the authors of the study presented in San Francisco, also presented this research at the Infectious Diseases Society of America conference, held in Philadelphia in November 1999.
"So we ask questions of why does the viral load stay low, and we started to look at their immune responses to see how their body handles HIV as compared to everyone else," Rosenberg says.
The Massachusetts General research suggests that it is possible to boost the immune system’s response when a person is treated with anti re troviral drugs within a few weeks of infection.1 Then, the antiretroviral treatment could be halted and later restarted to further boost the immune system.
"We’ve been trying to see if early treatment followed by strategic treatment interruptions can lead to a boost in HIV-specific immunity, and that was basically what we showed," Walker says. "You can take someone who is infected, treated very early to get a reliable increase in helper cell responses, and then you withdraw therapy, and that leads to a boost in cytotoxic t-lymphocyte response."
The hope is that this eventually could leave the immune system strong enough to suppress the virus without the drugs. (See story on other new immunity studies, p. 40.)
This may be a more realistic objective than to try to completely eradicate HIV from a person’s body, Walker says. "As long as the virus isn’t causing damage, does it matter if it’s still there?"
Other studies presented at the retroviruses conference also discussed strategies to boost immunity through scheduled interruptions of HAART.
Franco Lori, MD, director of the Research Institute of Genetic and Human Therapy (RIGHT) of Pavia, Italy, and Washington, DC, also presented a study that showed evidence that HIV can be controlled for eight weeks during treatment interruption of patients who had been receiving didanosine and hydroxyurea.2
Hydroxyurea used in stop-and-start treatment
Lori was the first researcher to propose using hydroxyurea to treat HIV for the purpose of boosting the effect of certain antiretrovirals, such as didanosine. Lori has treated more than 500 patients with the combination of hydroxyurea and didanosine, demonstrating that it’s possible to use a single retroviral successfully if it’s combined with hydroxyurea. Lori suggests hydroxyurea assists the immune response to HIV, although more research is needed to prove this hypothesis.
"All of our experience within this context is mainly with patients who were naive or not having any pre-exposure to antiretroviral drugs, and they were asymptomatic in most cases," Lori says.
Hydroxyurea was first used in the 1960s to treat chronic leukemia. More recently, it’s been approved for use in sickle cell anemia. However, its use for HIV is controversial because of the drug’s side effects, including a toxic effect on bone marrow.
More systematic studies need to be conducted before clinicians add hydroxyurea to patients’ regimens, says Richard Pollard, MD, professor of internal medicine, microbiology, immunology, and pathology at the University of Texas Medical Branch in Galveston. Pollard is a member of the Immunology Research Agenda Committee for the Adult AIDS Clinical Trials Group.
Pollard says Lori’s work is part of a body of research that addresses how to boost the host immune defenses against HIV in order to aid the response to antiretroviral drugs.
"I think multiple avenues are being explored, using interleukins, therapeutic vaccines, and this whole issue of starting and stopping therapy, hoping you can boost the patient’s own immune response against his virus," Pollard says. "That’s a much less developed area, but there is a lot of interest in the field on the concept of stopping therapy, and there’s a bunch of studies going on to examine that."
New research on immune system treatments is generating excitement because HAART has made it possible to boost the immune system after HIV infection. Previously, clinicians didn’t have the tools to control the virus, so immune therapies that were attempted before HAART were unsuccessful. Now that drugs can suppress the virus for years, immune treatments have a better chance of working.
"It’s really in the last several years that it’s a different kind of environment where we can go back and look aggressively at multiple interventions," Pollard explains.
Another interesting area of immunity research involves studying how the immune system is reconstituted during HAART.
Generation of immune cells studied
Researchers at Glaxo Wellcome Inc. in Research Triangle Park, NC, have been analyzing exactly what type of immune cells are generated when an HIV patient on therapy experiences an increase in CD4 cell count.
Using a T-cell receptor rearrangement assay, investigators were able to quantitate circular DNA fragments that can be used as markers of new T-cell production from the thymus, explains James Demarest, PhD, research investigator in virology and an immunology specialist at Glaxo Wellcome.
The Glaxo Wellcome group found comparable increases in CD4 cell counts in a study of 527 patients treated with combivir and either abacavir or indinavir. More notable, in a subset of 13 patients on the arm that included abacavir and eight being treated with indinavir, they found evidence that new T-cells were being created in both sets of participants.3
"So not only are there early increases in CD4 cell counts, but we’re talking about potential long-term benefits associated with the emergence of new T-cells from the thymus," Demarest says.
This discovery has important implications for long-term survival with HIV, particularly in terms of opportunistic infections.
"With HIV infection, you begin to have holes in your immune repertoire, and your T-cells have less success in fighting pathogens with which they had immunologic success in the past," Demarest says.
So if new T-cells are being added during therapy, this means the body’s immune system could recover its ability to recognize those pathogens to which it had begun to lose reactivity as a result of HIV damage. Because each T-cell is reactive to a unique region of one specific pathogen, i.e., one T-cell recognizes part of the influenza virus and another T-cell part of HIV, then it’s important that the body’s T-cells be as diverse as possible so as to cover all the various pathogens that might infect a person.
"As one loses T-cell populations over time, the ability of your body to recognize an invader decreases, the net effect being disease progression to AIDS-defining illnesses," Demarest adds.
The good news from the research was the finding that antiretroviral therapy with either abacavir or indinavir regimens resulted in a renewed diversity in T-cells, says Steve LaFon, MS, international product development leader at Glaxo Wellcome.
New technology for studying T-cells has made it possible for researchers to learn more about the body’s immune response to HIV after the initiation of antiretroviral therapy, LaFon notes.
"HIV specifically destroys CD4 T-cells, so by removing HIV or inhibiting the virus with drugs, treatment can help the CD4 T-cells to rebound," LaFon explains. "The important thing here is to determine that by reducing the virus, does it mean we’re heading toward a better immune system?"
That’s the question Glaxo Wellcome’s investigators and other researchers involved in HIV immune system studies are attempting to answer.
References
1. Atfeld M, Rosenberg ES, Eldridge RL, et al. Increase in breadth and frequency of CTL responses after structured therapy interruptions in individuals treated with HAART during acute HIV-1 infection. Abstract 357. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.
2. Lori F, Foli A, Maserati R, et al. Control of viremia after treatment interruption. Abstract 352. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.
3. Demarest JF, Lanier ER, et al. Evidence for comparable immune restoration between a PI-based triple antiretroviral therapy (IDV/COM) and an abacavir-based triple nucleoside therapy (ABC/COM): CNA3005. Abstract 331. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content