6th Conference on Retroviruses and Opportunistic Infections (CROI)
It's the Immune System, Stupid
Immunologic advances seen as the way to control HIV
Last year's conference was highlighted by Bruce Walker's presentation demonstrating that treatment with HAART very early after infection, usually defined as within 90 days, resulted in the preservation of a strong immunologic response to HIV. The 6th CROI emphasized many researchers' growing realization: THE key to controlling HIV infection is the immune system, not more and more antiretroviral drugs. In other words, it's the immune system, stupid!
Franco Lori presented the most provocative and fascinating information of the week, reporting on attempts to use strategic intermittent interruptions in HAART ("drug holidays") to boost immune response to HIV. The goal is to improve response to HIV to a level sufficient to control HIV replication, so that antiretroviral therapy is no longer necessary. The basis for attempting this approach is the case of a person known as the "Berlin patient," who was treated shortly after HIV infection with ddI, d4T, and hydroxyurea (HU). Although the patient had stopped his therapy for a short period of time, and then eventually stopped all therapy after 6 months, there has been control of HIV for 2 1/2 years.
The following three factors, identified by Dr. Lori, may have been important in this patient achieving good virologic control after HAART:
[Note: Perspective editors would add a fourth factor, that this patient had an excellent response to HAART, with very low HIV viral levels in the blood while on HAART.]
In order to study these factors further, Dr. Lori infected three monkeys with simian immunodeficiency virus, and then replicated the treatment regimen of the "Berlin patient," with the similar result that the monkeys were able to control their virologic infection when antiretroviral therapy was discontinued.
It is very important to emphasize that this was only one person, and treatment was started soon after HIV infection. Subsequently, Dr. Lori has treated three people with intentional interruptions in therapy, with treatment begun soon after HIV infection. While HIV became measurable in the blood, it took longer to come back after each break in therapy. The trial is still ongoing to see if eventually HAART can be stopped altogether.
Last year, Bruce Walker demonstrated that if HAART is begun within 3 months of HIV infection, a vigorous immune response to HIV can be preserved. He has attempted to stop therapy in people who were treated soon after HIV infection and who have had long-term suppression of HIV. However, this has resulted in the return of measurable HIV in the blood within a few weeks, and he has not attempted intermittent breaks in therapy, such as Dr. Lori is doing. It must be emphasized that most people who stop HAART have very rapid increases in HIV levels in the blood, whether therapy was begun soon after HIV infection or during the chronic infection stage. Also, there is a risk that intermittent therapy will lead to resistance, and permanent loss of control of viral replication. These are very preliminary reports demonstrating the increasing focus (finally) on augmenting the body's immune response to control HIV replication.
The rationale behind the research into intentional intermittent interruptions in HAART is based on the observations of Bruce Walker, and others, about long-term non-progressors (people infected with HIV for more than 10 years who retain normal immune system function on no therapy). Non-progressors show a strong immunologic response to HIV in both CD4 helper cell responses and CD8 cytotoxic lymphocyte (CTL) response, which may be the reason they can control HIV infection. Bruce Walker has shown that when people are treated soon after HIV infection, these immunologic responses to HIV are preserved, but in spite of that, when treatment is stopped, HIV usually begins to replicate and appear in the blood.
The idea is that short interruptions in treatment allow the immune system to be re-exposed to small amounts of HIV and mount an immunologic response, strengthening the ability of the body to eventually control HIV replication without HAART. This is essentially a type of auto-vaccination, and a rather novel approach to the treatment of any disease.
The argument for planned interruptions in the treatment of people who are treated during the chronic phase of HIV infection is even stronger, because specific immunologic responses to HIV are not observed even after 1 to 2 years of HAART in these people.
Other approaches being investigated include the administration of interleukin-2, which is an indirect stimulant of CD4 activity, administration of OKT3, an antibody that can stimulate CD4 cells into dividing, and the administration of HIV vaccines such as Remune. The rationale underlying attempts to stimulate resting, latently HIV-infected, CD4 cells into dividing is as follows. These cells would then begin producing HIV, which would kill them, and with effective HAART, the HIV produced would be prevented from infecting other cells.
A Tale of Two Trials of HAART Interruption
In one trial, Anthony Fauci and colleagues at the National Institutes for Health (NIH) identified three people who have received HAART and interleukin-2 for several years and who had no evidence of residual HIV-infected cells in their lymph nodes. However, they had just stopped HAART in these people, a couple of weeks before the Conference, to see if the virus would stay undetectable. It is possible that there is residual HIV in other areas of the body.
In another trial, interleukin-2 and the antibody OKT3 were used to purge the resting HIV-infected CD4 cells. However, even though they were able to show that they induced some of the resting CD4 cells to begin dividing and producing HIV, they could not demonstrate a decrease in the number of resting HIV-infected CD4 cells after the treatment.
It cannot be emphasized too much that these studies are very preliminary attempts to improve the body's immune response to HIV, whether by the use interruption of HAART as a form of auto-vaccination, the use of HIV vaccines, or other immune stimulants such as interleukin-2. No one knows if these approaches will work and what are the risks associated with them will be. Interleukin-2 has major toxicity in all people who receive it. Interruptions in HAART results in very rapid HIV replication in almost all people, and presents the risk of developing drug resistance, and the loss of benefits already achieved in the slow rebuilding of the immune system.
Very good data was presented by several groups showing that in almost all people on HAART, even when HAART is begun when the CD4 cell count is very low, there is a continued progressive improvement in the immune system. Recovery is seen in the numbers of memory cells (lymphocytes already programmed to defend the body against a specific infectious agent that the body has been exposed to in the past), as well as recovery of naïve cells (the very important lymphocytes that are able to mount an immune attack against infectious agents to which the body has not been exposed to in the past.)
Consequently, most people are recovering their immunity to fight off infections such as pneumocystis pneumonia (PCP), mycobacterium avium complex (MAC), cryptococcus, cytomegalovirus (CMV), and even Kaposi's sarcoma. The recovery of immune response can be so strong that a new syndrome has been described, called immune stimulation syndrome. People who have had tuberculosis or MAC sometimes develop high fevers and inflammation or swelling in areas of prior infection, due to a strong immunologic response to residual infection. At first, it was thought that there was reactivated disease at these sites, but now this is recognized as a strong immune response to the bacteria, which resolves in a short period of time.
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Abstract No. 323: Immunologic Reconstitution After 12 Months of Antiretroviral Therapy in Very Early Stages of Chronic HIV-1 Infection
This article was provided by Seattle Treatment Education Project.