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Shifting the Paradigm of Immunologic Control of HIV
M Connors
Natl Inst of Allergies and Infectious Diseases, NIH, Bethesda, MD
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Background: Our understanding of how HIV avoids immunologic control in most individuals remains incomplete and poses some of the greatest challenges to the rational design of effective vaccines and immunotherapies. A number of new techniques have enabled the direct measurement of quantitative and qualitative aspects of HIV-specific T-cells and the ability to recognize autologous HIV variants in infected individuals.
Methods: Peripheral blood lymphocytes from untreated patients (pts) with a broad range of plasma viral RNA concentrations were studied. HIV-specific CD8+ T-cells were studied using MHC tetramers, or stimulation with HIV peptides, vaccinia-HIV recombinant-infected B-cells, or CD4+ T-cells infected with heterologous or autologous viruses. HIV-specific CD4+ T-cells were stimulated with purified protein antigens or HIV peptides. The activation, cytokine and perforin production, cell cycle progression, and division of T-cells were measured by flow cytometry. Autologous viral variants were sequenced by limiting dilution RT-PCR of plasma virion RNA.
Results: Although high frequencies of HIV-specific CD8+ T-cells were present in long-term nonprogressors (LTNP) and progressors, only those of nonprogressors maintained a high proliferative capacity. This proliferation was coupled to increases in perforin expression. Differences in the ability to restrict HIV replication between HLA-B*5701+ LTNP and HLA-B*5701+ progressors were not attributable to sequence changes within known conserved B5701 restricted peptides or the ability to respond to autologous virus. In a separate cohort of 15 pts that maintain HIV-specific CD4+ T-cell responses equal to those of LTNP, proliferative responses were rapidly abrogated during viremia following 1–8 interruptions of therapy. Strong HIV-specific CD4+ T-cell responses were not predictive of the ability to restrict HIV replication in these pts.
Conclusions: These findings suggest that HIV-specific T-cells capable of activation, production of cytokines, and recognition of autologous virus in the context of infected CD4+ T-cells persist in patients in the ence of immunologic control of viral replication. The inability to restrict HIV replication in the majority of pts likely lies in qualitative properties of the cellular immune response that remain incompletely understood.
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