CTL RESPONSE IN ACUTE HIV INFECTION

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Acute HIV-1 infection is characterized by high level viremia, which subsequently declines to a quasi set-point. During the earliest stages of infection the majority of persons will develop an infectious mono- like syndrome with variable combinations of fever, rash, pharyngitis, oral and genital ulcers. Historically the majority of such cases have not been diagnosed, largely because of the non-specific nature of the symptoms and the lack of readily available assays to reliably diagnose the acute infection. The advent of viral load measurements has faciliated the early diagnosis of acute HIV infection, and the availability of highly active antiretroviral therapy has provided the opportunity to intervene therapeutically at the early stage of infection. Studies of acutely infected persons have indicated that the initial drop in viremia is temporally associated with the appearance of CTL, but these studies have been limited in number such that the breadth specificity of the CTL response in early infection is imcompletely understood. Furthermore, studies of the effects of early antiviral therapy on the ontogeny of the immune response have not been performed. Recent studies in the host laboratory have shown that early antiretroviral intervention results in the restoration of HIV-1-specific CD4 proliferative responses to both p24 and gp160. Since virus-specific CD4 cells are essential for maintenance of CTL responses in chronic viral infections, it is essential to determine not only the CTL response to HIV during acute infection, but also the effects of early therapy on this response. To address the immunopathogenesis of acute HIV infection, the AIDS Research Center at Massachusetts General Hospital has identified a cohort of 9 individuals with acute HIV infection. The hypothesis to be tested in the present proposal is that early antiviral therapy during acute HIV infection will be associated with preserved and improved CTL responses to HIV. The availability of this cohort of acutely infected patients affords the unique opportunity to study the immunology of primary HIV infection. To test this hypothesis a series of experiments will be performed to: 1) Characterize the magnitude and breadth of the CTL response in primary infection in acutely infected patients and compare these results with the CTL responses in acutely infected patients who were not treated with HAART; 2) Define the relationship of the CTL response with the development of CD4 help and the diminution of viral load; 3) Characterize the epitope specificity of CTL responses in primary HIV infection by cloning specifically stimulated CD8 cells; 4) Examine the ability of CTL responses elicited during acute infection to inhibit viral replication. These studies will provide important information regarding the immune mechanisms contributing to control of HIV replication during acute HIV infection.