Mad, Mad Science: Improved Clinical Outcomes Wrought By Immunosuppressive Medicine and Second-Rate Immune Responses - Where Will It All End?
Craig Sterritt has been tracking down the latest AIDS pathogenesis research - in addition to his project researching immune-based therapies. Here's some of what came out of the meeting in Yokohama.
An increasing number of reports are pointing to a correlation between the immune system's initial response to HIV infection and the course of subsequent disease. Preliminary evidence of the importance of so-called "viral trapping" within the lymph nodes - and the potential impact this has on disease outcome - was presented by the NIAID team of Fauci, Pantaleo and Graziosi.
Specifically, they showed how the state of the lymph node "architecture" in HIV-infected persons might determine whether or not - and how rapidly - they progress in their disease. According to his work with a small cohort of long-term non-progressors (LTNPs), Fauci concluded that the speed at which the lymph nodes are destroyed is determined by the efficiency with which they "trap" virus during initial infection. Specifically, in his work he noted that persons with more rapid disease progression had higher levels (> 1 log) of both HIV viral DNA and RNA in their lymph nodes than did non-progressors. Lymph node biopsies also revealed higher concentrations of formed germinal centers, indicative of heightened immune activity, in rapid progressors than non-progressors (who, in turn, demonstrated less germinal center formation than HIV-negative controls). While the possibility exists that the LTNPs were simply infected by less virulent strains of HIV, virus isolated from each patient was found
to be replication competent and infectious.
Drs. Fauci and Pantaleo discussed the probable significance of deleterious host factors within the lymph nodes. Activation of CD4+ T-cells in HIV disease has been associated with increased HIV replication, defective cytokine expression, and increased apoptosis, a form of cell suicide. Thus it is possible that higher concentrations of germinal centers, marking high levels of activated lymphocytes in close proximity to each other, might lead to more rapid disease progression. Conversely, Fauci proposed that the development of the "non-progressor" state may be the result of persistent low-level CD4+ activation and HIV replication in the lymph nodes, which would allow the virus to be consistently "seen" and controlled by the immune system, without overwhelming it in a state of hyperactivation.
Of course, even the most elementary understanding of immunology would indicate that an aggressive immune response to viral pathogens within the lymph system is desirable; but, in one of many unexpected twists of events, it seems possible that the non-progressor state - if not determined expressly by viral factors - may be attributable to either an over-sensitive, or under-powered immune system.
Supporting the correlation between CD4+ hyperactivation and disease progression was a presentation by Dr. Andrieu of France. His was a study in which open-label, low-dose prednilisone (a gluccocorticoid with anti- inflammatory and immunosuppressive activity) was administered to 24 CDC-class II (asymptomatic) and 20 CDC-class III (mildly symptomatic) HIV-infected persons (median CD4 cell counts upon entry: 438). After a peak gain of more than 200 CD4 cells at day 15, a median gain of > 100 cells was sustained throughout the year of follow-up. Levels of viral DNA, RNA, mRNA and p24 antigen remained stable over the course of the trial in all patients. Significant decreases were observed in serum activation markers (such as IgG, IgA and beta-2 microglobulin) as well as in cell-associated markers of CD4+ cell activation (DR and CD25 surface antigens). In addition, lymphadenopathies disappeared in 16 out of 20 class III patients, presumably indicating decreased lymph node activity.
Dr. Andrieu believes that CD4+ cell increases were attributable to a decrease in activation-induced apoptosis, which was significantly reduced in vitro following 15 days of prednilisone treatment. Whether the apparent rescue of CD4+ T cells from apoptosis alone - or from a combination of activation- and HIV-induced cellular events - effected the CD4+ cell increases, the results indicate that a moderate reduction in CD4+ sensitivity may improve immunologic parameters in the context of early- and middle-stage HIV disease.
The NIAID group's second report at Yokohama concerned the initial T-cell responses to HIV+ in individuals experiencing acute HIV infection reactions. According to the report, individuals who had rapid CD4+ T-cell declines and disease progression within one year of HIV infection demonstrated initial CD8+ CTL (cytotoxic "killer" T-lymphocyte) immune responses that were intensively directed at a very limited number of HIV epitopes (peptide sequences on the surface of a particular pathogen), while individuals with better immunologic and clinical outcomes demonstrated a more broad-based CTL response to a larger variety of HIV epitopes.
For example, the two patients (N=6) with rapid disease progression had as high as 40% of their circulating T-lymphocytes bearing homologous T-cell receptor (TCR) V§ sequences during acute HIV infection. By contrast, a patient who showed no CD4+ T-cell depletion or other signs of immune deterioration was found to have mild-to-moderate activation of nearly all V§ subsets. Because HIV, like all viral and bacterial pathogens, can be recognized by the immune system through many epitopes, these experiments suggest that a broad-based, multi-targeted T-cell response might be more effective at recognizing and controlling infection.