During the course of acute HIV-1 infection, viral replication is generally contained by the development of virus specific immune responses. However, only a minority of infected individuals achieve long term control in the absence of other interventions. These individuals, so called long term nonprogressors, develop, effective anti-HIV-1 immunity characterized by effector CD4 helper cells and cytolytic CD8 T cell responses. In contrast, the majority of chronically infected individuals have a paucity of HIV-1 specific proliferative responses along with dysfunctional CD8+ T cells. The mechanisms by which HIV-1 adversely affects the immune system are unclear but they probably start during the early phases of infection. We speculate that malfunction of the antigen presentation process by dendritic cells, inappropriate hyperactivation of T cells and apoptosis, and/or deletion or unresponsiveness of HIV-1 specific CD4 clones are the responsible factors. This proposal will take advantage of the large numbers of acute and early HIV infections being identified at NYU/Bellevue and affiliated hospitals, to test the hypothesis that antigen presenting cell function, in particular of dendritic cells is seriously compromised during the initial stages of infection.
The specific aims are to: (1) Characterize DC subsets in peripheral blood and mucosal lymphoid tissue of HIV-1 infected individuals during primary infection. DC subsets. Plasmacytoid DCs (pDCs) and CD11c+ myeloid DCs will be enumerated at the time of diagnosis and tracked longitudinally in each subject for up to five years; (2) Assess the function of peripheral blood and mucosal lymphoid DC subsets during primary infection and following initiation of therapy and (3) To establish whether DC precursors, in particular monocyte subsets, are compromised during primary infection. All DC subsets will be evaluated for the presence of HIV-1 infection, their ability to differentiate into mature phenotypes, and their ability to present antigens to T cells. These data should provide important new information regarding the relative numbers of DCs during acute and early infection, whether they are infected with HIV-1 and whether their function is seriously compromised during infection. In particular we will address the possibility that DCs are responsible for the T cell dysfunction that is observed in the CD4 compartment in early infection. DC number and function can be enhanced in vivo by certain modalities, therefore the data obtained from this study may support implementation of approaches to enhance DC activity during acute infection.
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