Characterization of Programmed Death-1 Homologue-1 (PD-1H) Expression and Function in Normal and HIV Infected Individuals

Abstract

Chronic immune activation that persists despite anti-retroviral therapy (ART) is the strongest predictor of disease progression in HIV infection. Monocyte/macrophages in HIV-infected individuals are known to spontaneously secrete cytokines, although neither the mechanism nor the molecules involved are known. Here we show that overexpression of the newly described co-stimulatory molecule, PD1 homologue (PD-1H) in human monocyte/macrophages is sufficient to induce spontaneous secretion of multiple cytokines. The process requires signaling via PD-1H as cytokine secretion could be abrogated by deletion of the cytoplasmic domain. Such overexpression of PD-1H, associated with spontaneous cytokine expression is seen in monocytes from chronically HIV-infected individuals and this correlates with immune activation and CD4 depletion, but not viral load. Moreover, antigen presentation by PD-1H-overexpressing monocytes results in enhanced cytokine secretion by HIV-specific T cells. These results suggest that PD-1H might play a crucial role in modulating immune activation and immune response in HIV infection.

VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis

“…For example, spontaneous cytokine production was found in monocytes from HIV-infected individuals that overexpressed VISTA. Furthermore, these monocytes were able to increase cytokine production by HIV-specific T cells (15). Investigators in our laboratory have shown that VISTA functions as a ligand on myeloid cells to suppress T cell activation through a putative VISTA receptor (9,10).…”

“…VISTA shares homology with PD ligand 1 and PD-1 (9,12) and can suppress T cell activation in vitro (9). Recently, VISTA was shown to affect the activities of myeloid cells as a receptor (15), and a very recent study showed involvement of VISTA in the uptake of apoptotic cells (13). These data suggest that VISTA activities could exert a profound effect on the development and progression of lupus.…”

Role of immune activation in progression to AIDS

“…HIV results in a shift from “classical” CD14++CD16− to “non-classical” CD14+CD16+ and “intermediate” CD14++CD16+ monocytes, which are associated with an inflammatory phenotype [40–42] and greater viremia and/or CD4+ T cell depletion [42, 43]. High expression of the PD1 homologue (PD-1H), which is associated with increased production of TNF, IL-1β, and IL-6, may also contribute to the pro-inflammatory state of these monocytes [44]. CD16+ non-classical and intermediate monocytes have a high migratory capacity, which has been attributed to expression of the chemokine receptors CCR2, CCR5, [45, 46] and CX3CR1 [47].…”

Immune Activation in HIV Infection: Friend or Foe

“…Several immunological features play a crucial role in causing progression to AIDS of which chronic immune activation is the most prominent reason [2,3]. It is characterized by increased proinflammatory cytokines; increased expression of T cell activation or exhaustion markers like CD38 and HLA-DR, Programmed Death-1 (PD-1), Tim-3, CTLA-4 and newly described immune regulator PD-1 Homologue (PD-1H) that may interfere with on-going HIV specific cell responses [4][5][6][7]. It is now believed that levels of chronic immune activation predict the progression to AIDS independently from viral loads or CD4 + T lymphocyte counts.…”

“…Blocking of negative regulatory molecules like PD-1 has received considerable attention due to partial restoration of immune functions upon modulation of these receptors [6]. Recently a new member of PD-1 family called PD-1 Homologue (PD-1H) was implicated to play an important role in pro inflammatory cytokine secretion and enhancing immune responses to HIV antigens [7].…”