Sixth International Congress Drug Therapy in HIV Infection 17-21 November, 2002 Glasgow, UK

[ABSTRACT:]On the basis of the recent advances in the characterization of HIV-1-specific CD4 and CD8 T cell immune responses, it is clear that the type of the immune abnormalities associated with HIV-1 infection are both quantitative and qualitative. There is a selective loss of the CD4 T helper function and likely a reduction of the pool of CD4 T cells with effector function. With regard to CD8 T cells, there is a skewed maturation with almost the absence of terminally differentiated cells that may explain the potential defect of perforin that is expressed at higher levels in cells at the late stages of differentiation. Is there a link between the qualitative abnormalities observed in CD4 and CD8 T cells? The answer is certainly affirmative. The likely scenario is that these qualitative abnormalities are initiated by the defect of CD4 T helper function. The absence of HIV-1-specific CD4 helper T cells may be responsible for the establishment of a quantitative defect of the pool of effector CD4 T cells that eventually will progressively disappear over timesince the pool of precursors cells, e.g. CD4 helper T cells, is absent and cannot guarantee their continuous replenishment. The absence of HIV-1-specific CD4 helper T cells is also likely associated with the defect of several soluble factors that are critical for the adequate maturation of memory CD8 T cells with effector function and for their persistence over time.

The current challenge is to develop strategies that may correct the immunologic defects mentioned above. Unfortunately, the potential contribution of antiretroviral therapy to the correction of the immunologic abnormalities is extremely limited. Antiretroviral therapy is capable of restoring CD4 T cell counts from a quantitative standpoint in patients with chronic infection but seems to have little impact on the restoration of an effective HIV-1-specific immune response. The strategies of immune-based interventions that have received particular attention are those aimed at augmenting HIV-1-specific immunity after immunization with virus subunits (virus proteins) and/or virus vector expressing different HIV-1 proteins. These immunization strategies are also known as therapeutic vaccine and their main objective, at least in patients with chronic infection, has to be the development of de novo immune responses. Since the type of immune response already present is not able to control HIV-1 replication and all the evidences indicate that this immune response is extremely vigorous, at least with regard to the CD8 T cells, it is unlikely that a quantitative increment of the potency will confer a protective capacity to the immune response. In particular, it is fundamental to stimulate HIV-1-specific CD4 helper T cell responses that are absent and/or severely impaired in patients with chronic infection. The restoration of CD4 helper T cells, e.g. therefore of the virus-specific CD4 T cells that function as precursors for the other populations of memory T cells, likely may insure the continuous replenishment of the population of memory CD4 T cells with effector function and the complete maturation of virusspecific memory CD8 T cells by the optimal secretion of factors such as IL-2 and IL-15.

In conclusion, there is a major need for the development of immune-based interventions. These interventions are complementary to antiretroviral therapy, which remains the primary treatment intervention in order to achieve effective suppression of virus replication, and may be extremely instrumental for the long-term control of virus replication.

Presenting author: Giuseppe Pantaleo

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1 Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland

2002-11-17
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