The Body Covers: The 7th Annual Clinical Care Options for HIV Symposium
Advances in Immune Reconstitution
It was clear that this is a "hot topic" these days, because by the time Dr. Cliff Lane (National Institutes of Allergy and Infectious Diseases, Bethesda) gave his talk, two or three other speakers had already shown his slides.
There are a number of forces working together and against each other which determine the immune function of the HIV-infected individual. These include the effect of HIV itself, which may or may not be modulated by antiretroviral therapy, the host's immune response to HIV infection, and the ability of the immune system to regenerate itself if HIV is suppressed. Characteristics of HIV-related immunodeficiency include not only the decline in numbers of CD4 lymphocytes, but also a loss of diversity in the CD4 cell repertoire.
There are two types of CD4 lymphocytes: naive cells (CD45 RA) and memory cells (CD45 RO). Naive cells are cells that have not recently encountered antigen, thus they usually carry antigen receptors for less common antigens. Memory cells, on the other hand, are cells with antigen receptors for more common and recently encountered antigens. Naive cells should be distinguished from undifferentiated cells, which have not yet developed antigen specificity. Thus, in a T-cell pool, CD4 cells that are used frequently (memory cells) increase in number, while naive cells persist in low numbers. New T-cells are generated either from new stem cells in the thymus or through peripheral expansion of T-cell clones that are already present. Because in the adult little thymic tissue remains, the latter mechanisms accounts for the bulk of new T-cell formation.
With advancing HIV infection and declining CD4 cell count, naive T-cells account for a smaller proportion of the CD4 cell pool. It has now been demonstrated that if viral replication has been shut off through the use of effective antiretroviral therapy, those CD4 cells already present will expand. If that pool includes naive cells, they will expand, but in patients with advanced disease those CD4 cells that do expand may be comprised primarily of memory cells. Thus, in such patients the CD4 expansion that occurs may be almost exclusively an expansion of memory cells, leaving patients with much higher CD4 cell counts but with no improvement in their ability to respond to uncommon antigens. It is for this reason that it is now felt that immune competence should be defined by the lowest CD4 count that a patient has had.
Dr. Lane went on to discuss the potential for immunotherapy to increase the likelihood of immune restoration. Some investigational strategies include adoptive transfer of syngenetic lymphocytes or of lymphocytes genetically modified to resist HIV infection. Another that has been better studied is the use of interleukin-2 (IL-2), a T-cell growth factor. IL-2 was initially studied using a 21-day infusion. The peak effect was seen at 7 days, and then the effect on CD4 cells declined. It was learned that this decline was because of an upregulation in IL-2 receptors, resulting in a significant decrease in IL-2 levels, one which could not be overcome by increasing the dose because of the toxicity of the drug.
This finding led to the idea of infusing IL-2 intermittently, with "rest periods" between infusions. IL-2 was given in five-day infusions every eight weeks. This was associated with a progressive rise in CD4 count, as well as transient elevations in viral load during the infusion. IL-2 resulted in expansions of both naive and memory T-cells.
Randomized trials of IL-2 now involve using antiretroviral therapy with or without IL-2, in order to suppress viral replication and blunt the rise in viral load seen with IL-2 alone. Thus far, the strategy appears to be effective. Concern has been raised about whether patients with high CD4 counts as a result of IL-2 may in fact be experiencing opportunistic complications atypical for their CD4 count, but in fact an analysis of clinical trials using IL-2 demonstrates that complications are occurring at the expected CD4 counts. Studies using lower doses of IL-2 administered by subcutaneous injection rather than intravenous infusion look promising.
This article was provided by The Body PRO. Copyright © Body Health Resources Corporation. All rights reserved.