Plasmacytoid dendritic cells in HIV infection: striking a delicate balance

Abstract

pDC are the most potent IFN-alpha-producing cells in the body and serve as a vital link between innate and adaptive immunity. Deficiencies in pDC function were among the earliest observations of immune dysfunction in HIV-1 infection. Herein, we review the status of pDC in individuals with HIV-1 infection and the potential role of these cells in pathogenesis. We begin by reviewing the basic properties of pDC and then discuss the compromise in circulating pDC numbers and function in early and viremic HIV-1 infection and mechanisms that might account for their depletion in HIV-infected patients. In addition, we review the evidence that chronic production of IFN-alpha, probably through the chronic activation of pDC, is central to the immune activation that is so detrimental in HIV infection. Finally, we discuss the importance of balance in pDC numbers and function and the potential value of using absolute pDC counts and function as a biomarker, along with CD4(+) cell counts and VL in HIV-1-infected patients.

Figure 1.

Fate of pDC in HIV-infected individuals. pDC enter the circulation from the bone marrow, where they migrate to the lymphoid tissue directly or circulate until they encounter live or defective HIV-1 or other pathogens. Encounter with HIV-1 leads to pDC activation and production of IFN-α, partial or full maturation of the pDC, apoptosis of the pDC, or fusion of the pDC with HIV-infected CD4⁺ cells. This can result in migration of the pDC to the LN and replacement with immature pDC from the bone marrow. At later times, we hypothesize that bone marrow output of nascent pDC may decline as a result of replicative exhaustion. High levels of IFN-α induce TRAIL expression on pDC, making them into IKpDC as well as DR expression CD4⁺ T cells. This in turn is hypothesized to lead to killing and depletion of infected T cells and T cells that have encountered defective virus as well as death of the pDC.

Figure 2.

Keeping the balance of pDC activity in HIV infection. Loss of a balanced pDC response is of great importance in HIV-1 pathogenesis. Depletion of pDC numbers and their functional activity can have a number of effects that lead to HIV pathogenesis. In addition to limiting virus replication through the production of IFN-α, pDC function is critical for licensing effective NK and for preventing pDC and T cell apoptosis. Loss of pDC in viremic HIV-1 infection (right pan in the balance) results in increased virus replication, decreased killing of virus-infected cells, as well as pDC and CD4⁺ T cell death, all leading to HIV pathogenesis. On the contrary, chronic stimulation of pDC leads to expression of TRAIL on CD4 T cells and pDC and the expression of DRs on CD4⁺ T cells, which contributes to the induction of apoptosis of uninfected CD4⁺ T cells through IKpDC (left pan of the balance). Additionally, chronic stimulation of pDC driven by continual HIV production can lead to the generation of Tregs through the induction of IDO, which attenuates the immune response when it is most critical and fosters an increase in viral replication. However, the correct balance of pDC activation and the subsequent functions of pDC will result in proper antigen presentation and elimination of HIV-infected cells and decreased viral replication and allow for the survival of pDC and CD4 T cells that are required for an effective immune response (“balance”). We hypothesize that steps to prevent this chronic stimulation of the pDC, perhaps by early antiretroviral therapy, will preserve normal, protective pDC function.