Reports from the 6th Conference on Retroviruses and Opportunistic Infections
Antiretroviral drugs were to have signaled a new era in the fight against HIV, with hope of its elimination. Unfortunately, hope has fallen as a rising number of HIV-infected individuals have developed resistance to these drugs. After the World AIDS Conference in 1996, people began to whisper about HIV eradication. However, information discovered since then has led most researchers to talk about containment, not eradication.
With treatment choices narrowing, immune-based therapy has become the new focus. In the past, the focus was on antiretroviral drugs, but in the last few years there have been major advances in immunologic research. Several reports given at the 6th Conference on Retroviruses and Opportunistic Infections (CROI) in Chicago show the shift in focus.
Studies of people who have been infected for over 10 years, without significant damage to the immune system, known as long-term non-progressors (LTNPs), have produced insights into how the immune system might control HIV infection.
The body has two major immunologic systems. The first system fights bacteria and uses B cells, a type of lymphocyte (white blood cell), to form antibodies. The second system primarily fights viruses and cancers. It uses CD8 lymphocytes, which can directly attack and kill cells infected with a virus or a cancer. The CD8 lymphocytes are called cytotoxic T-lymphocytes (CTLs). The CD4 lymphocytes or CD4 helpers are essential to initiating and assisting the direct killing of HIV-infected cells by CD8 cells. This process is referred to as the CTL response. Infection with HIV results in a loss of CD4 lymphocytes, breaking a critical link in the immune defense.
HIV infection results in the production of anti-HIV antibodies. (Detection of these antibodies is the basis of the test to determine HIV infection.) However, why these antibodies are not effective in controlling HIV replication remains a mystery. At last year's CROI, Harvard's Bruce Walker showed that LTNPs had a very high HIV-specific CTL response -- in the test tube, their CD8 cells were able to multiply and kill specific cells infected with HIV. Also, their CD4 lymphocytes responded very well to HIV. To control HIV infection without drugs, a strong specific response to HIV in both CD4 and CD8 lymphocytes is needed. What is not known is why this response occurs only in about 10 percent of people infected with HIV.
Dr. Walker also showed that people treated within a few months after they acquire HIV infection (referred to as therapy for primary infection), were able to preserve a very strong HIV-specific CD4 and CD8 CTL response, as measured in the laboratory. (Without early treatment you would only expect to see this response in about 10 percent of people.) The clinical implication is that early therapy may allow discontinuation of highly active antiretroviral therapy (HAART) with subsequent control of viral replication. In other words, in theory, using early HAART may create LTNPs. The real test is whether HAART can eventually be stopped. Dr.Walker's group is beginning to test this, but other researchers have reported prompt viral replication in similar subjects when their HAART was stopped.
In contrast, people who have been infected with HIV for a long time (chronically infected) show very little or no evidence of an HIV-specific CD8 CTL response. Data presented at the 6th CROI showed that even with long-term viral suppression to below limits of detection, there was no recovery of the CD4 and CD8 CTL response. HAART therapy did not lead to the development of HIV-specific immunity. So now the focus of immunologic research is on creating an HIV-specific response in people whose immune systems have been strengthened by HAART.
The hope that HIV could be completely eradicated by HAART was extinguished last year when several research groups showed that HIV-infected cells still remained in the lymph nodes of people who had been on HAART for over 1 to 2 years and who had no detectable virus in their blood, even when measured by the most sensitive tests. Generally, HIV replicates inside a cell and kills it, which releases HIV, which then infects other cells. The theory was that if new cells were prevented from becoming infected with HIV, eventually all of the HIV-infected cells would disappear. However, it was found that there are a relatively small number of CD4 lymphocytes in the lymph nodes that contain the HIV genes but are not actively producing HIV. These cells (called replicative competent, latently infected lymphocytes) are capable of producing HIV at some time in the future. It is thought that these are the cells responsible for the rapid HIV replication seen in most people when HAART is stopped.
David Ho presented data that showed these cells may gradually decrease in number over time on HAART, but that it would take over 8 to10 years for all of them to disappear. However, researchers from the National Institutes of Health (NIH) presented data that contradicted this; they found no change in the number of latently infected lymphocytes in the lymph nodes over time. This pool of latently infected cells may form at the time of initial HIV infection, a theory that is supported by data from Bruce Walker's studies of people who were treated early after HIV infection, and who showed no drug resistance in the HIV produced by their latently infected cells.
Realizing that viral rebound and viral resistance are a major problem with HAART has refocused attention on attempts to strengthen the natural immune control of HIV. There are two general approaches being tried: general boosting of the immune system and specific stimulation of HIV immunity. Compounds used to boost general immunologic responses include interleukin-2, interleukin-12, and interferon. Approaches used to strengthen HIV-specific immunity include the Remune vaccine (an inactivated, whole virus vaccine) and measures to increase the number of HIV-fighting CD8 cells.
Anthony Fauci presented at intriguing look at people who have been treated for years at the NIH with HAART and interleukin 2 (IL-2), a nonspecific immune-boosting agent. IL-2 must be injected, either intravenously or under the skin. It causes a very significant flu-like syndrome and many people are not able to tolerate it. However, IL-2 greatly increases CD4 counts, an effect that often persists long after IL-2 was administered. Dr. Fauci identified three people who have no evidence of latently HIV-infected lymphocytes. They showed long term-viral suppression on HAART and IL-2 for an average of 39 months. The three had just stopped HAART 3 weeks before the 6th CROI, so we do not yet know if the virus will reappear from other potential reservoirs such as the testes or brain. (Disappointingly, follow-up data presented at a May conference reported that some of these people have had reappearance of HIV in their blood.)
Fred Valentine presented data from an ongoing trial administering the Remune vaccine to people on HAART with good viral suppression. His data showed increased immunologic responses to HIV in the test tube. He also showed that the immunity thus generated responded to types of HIV other than the strain used to prepare the vaccine. Longer clinical trials will be necessary to determine if there is any clinical benefit to vaccinating people already infected with HIV. The possible clinical benefit is better, and hopefully longer, suppression of viral reproduction when a vaccine is added to HAART. Also, it may be possible to stop HAART after vaccination because the strengthened immune response to HIV might be able to contain or prevent viral replication.
Researchers from Seattle presented data published in January detailing a unique immunologic approach. They isolated HIV-specific CD8 cells from people with HIV infection and were able to multiply these cells in the lab many, many times over a period of a week or two. They then marked these cells and gave them back to the people they were isolated from. Although their viral levels dropped significantly, the benefit lasted only a short time. Nonetheless, the researchers are also attempting a similar trial isolating CD8 cells that can attack cytomegalovirus (CMV).
A group from Dallas reported on a new way to attack the latent HIV-infected cells. They injected people with a monoclonal antibody (an antibody grown in the lab), OKT3, which activates resting CD4 cells and causes them to reproduce. The theory is that when the activated CD4 cells reproduce, they make HIV, which will kill them, and that HAART will prevent the HIV produced by the activated CD4 cells from infecting other cells. The Dallas group showed the expected boost in HIV production after monoclonal therapy, but the number of latent HIV-infected cells did not decrease. This treatment also had major side effects.
While none of these approaches have proven beneficial in boosting HIV-specific immunity, or decreasing the residual pool of HIV-infected cells, they are exciting attempts to improve the immunologic control of HIV. In the next year or two there will be several other trials evaluating these and similar approaches.
Several studies presented at the 6th CROI showed that there is significant continued improvement of the immune system on HAART. Many people were concerned that the damage to the immune system caused by HIV was irreversible (the main reason some recommend starting HAART very early). However, in the last year many studies have shown that in most people on HAART, all components of the immune system improve.
The body is continually making new lymphocytes, naïve immune cells that have not yet been programmed to fight a specific invading organism. When a naïve cell is exposed to a new invader, it becomes specifically programmed to fight that organism, and makes many copies of itself. These cells are called memory cells and react only to the organism they are programmed to fight. Naïve cells are essential to react to new invading organisms. Initially, after HAART therapy, there is a significant increase in the memory cells, and not the naïve cells. However, many studies have now shown that over the first year, and continuing after that, there is a steady, slow increase in the number of naïve cells. This means that if viral production is kept suppressed, the immune system will partially recover while on HAART. (The risk of stopping HAART, even for a short period of time, is that HIV replication could very quickly wipe out the gains that may take years to be fully realized.)
New techniques are allowing investigators to measure specific immune responses to organisms such as pneumocystis carinii (which causes PCP, or pneumonia), mycobacterium avium (which causes MAC infection), and CMV. In most people on HAART, immunologic responses to these organisms improve. (One study showed that the few people who developed CMV while on HAART did not show improvements in laboratory-measured CMV immunity either.) In addition to strengthening the effectiveness of the memory cells that are already programmed to fight these specific organisms, the new naïve cells are capable of mounting their own immunologic attack against these organisms.
Since immunity to specific organisms improves on HAART, the question is whether a person can stop taking the medications previously needed to prevent these infections. This would include prophylaxis for PCP, CMV, and MAC. There are now eight studies, including a large study presented at the 6th CROI by Spain's Dr. Lopez, which show that for people on HAART who have CD4 counts above 200, it is probably safe to stop PCP prophylaxis. Other studies have shown that stopping prophylaxis for CMV is safe for most people if the CD4 count remains above 200 to 250. However, there are several cases of CMV in people with CD4 counts above 200. It may be that within the next year a laboratory test will be done to check for immunity to CMV before prophylaxis is stopped.
Some people who develop resistance to HAART appear to do better clinically after stopping HAART than they did before HAART. Some have even had increases in CD4 cells in spite of rising HIV viral loads, as reported by a Swiss group and by Steven Deeks from San Francisco General Hospital. It may be that the drug-resistant virus is weaker, and less able to replicate. However, it is also possible the immune system is better able to contain the resistant virus. This raises the interesting possibility that there may be treatments that could render HIV more susceptible to immunologic control.
There is increasing emphasis on immune-based therapy for HIV as the long-term limitations of HAART become more apparent. The short- and long-term side effects of HAART, drug resistance, failure to eradicate HIV, and the large of number of pills and complicated schedules makes it unrealistic to assume that people can continue on these regimens for many years. In addition there is a lack of good drugs for people who fail the protease inhibitors that are the main component of HAART.
For years, HIV activists have been demanding greater emphasis on immunologic approaches. There are many trials that are ongoing, or starting soon, that will evaluate intermittent therapy and HIV-specific and nonspecific immune-based therapies. The goal is to improve the body's immune response and control of HIV so that HAART can be more effective, or possibly even stopped. The next year or two should be very exciting as the results from these trials begin to be known. We are seeing significant advances in immunologic techniques and immune-based therapies are finally getting the attention they deserve.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.