Use It. Lose It.
Tantalizing Research Paper Contemplates The Restoration of HIV-Specific 'T-Help' After HAART
‘An argument for immediate therapy?’
The hallmarks of HIV infection and AIDS are a gradual deterioration of the immune system and the subsequent development of opportunistic infections that debilitate and eventually kill those infected with the virus. The deterioration of the immune system in HIV infection, TAG's Gregg Gonsalves reminds us, is both quantitative and qualitative. On the heels of two intriguing research papers, one by Harvard U.'s Bruce Walker; the other, by U. Texas's Louis Picker, Gregg helps to integrate these latest findings into the existing model of HIV pathogenesis.
Long before the actual depletion of absolute CD4+ T-cell numbers, functional deficits in the ability of the immune system to properly respond to HIV and common pathogens begin to appear. This derangement of the immune response is an important part of the pathogenesis of the disease. The functional impairment of the immune system-in particular the ability of CD4+ T-cells to proliferate and produce cytokines in response to antigenic challenge from HIV and opportunistic pathogens like cytomegalovirus (CMV)-is the subject of two recent papers. These studies come at the topic from a unique angle: they look at cases in which immune function is retained in HIV disease.
By exploring these special circumstances, both papers provide clues to how we might restore immune function in people with HIV and beat back the virus. The first study, by researchers working under Bruce Walker at Massachusetts General Hospital in Boston, looked at HIV-specific CD4+ T-cell responses in long-term survivors of HIV infection. These long-term survivors have been infected for up to 18 years, have normal CD4+ numbers and undetectable viral loads, have shown no clinical progression of disease and have never been on antiretroviral therapy.
Generally in HIV infection, virus-specific CD4+ responses are low or non-existent. This may be because HIV-specific CD4+ cells are killed off during primary infection since these cells are the first to be called up to fight off the viral invader. In mouse models of chronic viral infection, though, vigorous CD4+ T-cell activity is important in maintaining an effective immune response. Based on this evidence, Walker's team wanted to see if long-term survivors of HIV infection had unusual CD4+ cell responses. Their hunch was right. The group at Mass. General found strong HIV-specific CD4+ proliferative responses and the concomitant production of anti-HIV cytokines by HIV-specific CD4+ cells in long-term survivors of HIV infection. Walker's group also found that the strongest HIV-specific proliferative responses correlated with the lowest viral loads in this cohort (although no such correlation could be made in a second cohort analyzed). Many of these individuals also had robust cytotoxic T- cell and antibody responses-another sign that their immune systems might be holding the virus in check.
After establishing the importance of the CD4+ proliferative response in controlling HIV infection, Walker's team also wanted to see if they could reproduce this phenomenon in people recently infected with the virus. By initiating potent antiretroviral therapy during primary infection, Walker's team was able to generate strong proliferative responses to HIV in their patients. This was probably accomplished by rescuing HIV-specific CD4+ T-cells from their death during the high viremia usually associated with this phase of the disease. It has already been shown in other studies, however, that people who initiate therapy later in the course of the disease generally are not able to recover robust HIV-specific responses-probably because they lost these HIV-specific CD4+ cells during primary infection. Does this mean that unless therapy is initiated during primary infection, robust HIV-specific CD4+ T-cell responses are lost forever-except for those lucky few who happen to be long-term survivors of HIV infection? Maybe not. Walker's group holds out the possibility of restoring the proliferative response in these patients by immunizing them with HIV vaccines. In a monkey model, strong proliferative responses to HIV were generated by administering a DNA vaccine to these animals. Perhaps the concept of therapeutic immunization in HIV infection merits another look-in order to see if we can boost certain immune responses in people on potent antiretroviral therapy.
Louis Picker at the University of Texas Southwestern Medical Center is looking at the nature of the functional deficits in the immune response in AIDS. Picker's group is using a novel technique that employs flow cytometry to measure and describe antigen specific memory T-cell responses. They are hoping to gain some "insight into the mechanisms of both immune destruction and reconstitution" by examining the response of antigen specific T-cells throughout the course of HIV disease. They have focused their investigation on the antigen specific CD4+ T-cell response to CMV because of the prevalence of this opportunistic infection in people with HIV infection.
T-cell responses to many common pathogens such as tetanus, influenza and candida are lost during the course of HIV disease. Surprisingly, instead of finding diminished CD4+ T-cell responses to CMV in patients with HIV disease, Picker's group found markedly increased responsiveness to this pathogen. Forty percent of patients, regardless of disease stage, had 3 times the normal level of CMV reactivity while the rest had at least normal responsiveness to CMV antigens. Responsiveness to standard recall antigens where reduced or absent in Picker's cohort of HIV+ subjects.
Why is Picker's group seeing heightened reactivity to opportunistic pathogens even in substantially immunocompromised individuals? Picker explains this phenomenon by invoking recent research on the nature of T-cell memory responses. According to the latest theory, the number and function of any given antigen-specific T-cell is governed by a shifting microenvironment in the tissues where these cells reside. The most important factor determining the fate of these cells is a competition for a finite number of survival "niches" in the body. One of the most potent influences on the survival of a given antigen-specific T-cell is antigen availability. This means that T-cells that encounter their given antigen more regularly will outcompete those T-cells that rarely or never come into contact with their antigen. T-cells specific for a given antigen may even be driven into extinction by the expanding number of T-cells with other specificities.
In HIV-uninfected people, the shifts in the repertoire of T-cell memory response due to this phenomenon are probably very slow due to the "relatively low-level microbial pathogen environment of Western society." In HIV infection, however, T-cell turnover is greatly accelerated; and encounters with opportunistic pathogens, greatly increased. Picker surmises that the high rate of T-cell turnover in HIV infection and the high rates of exposure to CMV in HIV-positive subjects may be driving the survival of CMV-specific T-cell clones at all stages of the disease. In Picker's model, CMV-specific T-cells would outcompete T-cells specific for less commonly encountered pathogens like mumps or tetanus. This mechanism may be an attempt by the immune system to compensate for the overall decline in CD4+ T-cells in HIV infection by promoting the survival of T-cells that are reactive with antigens that are more common and are more likely to be a threat to the host. When even this compensatory mechanism cannot provide enough T-cells capable of fighting off a given pathogen, the immune response may fail and opportunistic infections develop late in the disease.
What are the therapeutic implications of Picker's work? Picker is now trying to find out if T-cells specific for CMV are lost late in disease as this homeostatic mechanism of T-cell replacement loses its battle against HIV infection. If they are not lost, Picker would like to see if potent antiretroviral therapy will be able to reinstate a substantial population of CMV specific clones which are able to fend off clinical CMV disease. Tantalizing hints come from a recent study of highly active antiretroviral therapy (HAART) in which patients were able to go off maintenance therapy for CMV without recurrence of CMV disease. Are their immune systems bouncing back? It appears that they might be. Even patients with low proliferative responses to CMV might be able to be be "vaccinated" with CMV antigens to bolster their bodies' anti-CMV defenses after successful antiretroviral therapy. These are some of the intriguing possibilities that are flourishing in the new world of HIV immunology in the era of HAART.