Irreversible Loss of pDCs by Apoptosis During Early HIV Infection May Be a Critical Determinant of Immune Dysfunction

Abstract

The dendritic cell subsets myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) play an important role in HIV pathogenesis. While pDCs play a major role in the innate immune response, mDCs are important for induction of the antigen-specific immune response. We studied pDCs and mDCs at different stages of HIV infection, and found that there were decreased percentages of pDCs and mDCs in the advanced stage of the disease (p < 0.0001), and that slow progressors did not show as great a decrease as more healthy individuals. Persons who had acquired infection within the last year showed a normal mDC percentage but a lower pDC percentage (p = 0.0092) than healthy individuals (0.16%). pDC percentages in those with late-stage disease did not revert to normal after successful antiretroviral therapy (ART), whereas mDC percentages reverted to levels comparable to those seen in the healthy population (0.08% pre-ART to 0.18% post-ART; p < 0.0001). The pDC population had high levels of apoptotic markers in those with recent (p = 0.0025) and advanced (p = 0.0012) HIV infection, with no difference in their migratory capacity from controls and slow progressors, indicating that apoptosis is the major mechanism of declining pDC numbers in the circulation. mDCs showed increased levels of apoptotic markers (p = 0.0012), as well as migration (p = 0.03), in those with advanced-stage disease compared to controls, suggesting that both migration and apoptosis contribute to the decline seen in mDCs in the circulation. The irreversible loss of pDCs due to apoptosis seen early in HIV infection may be responsible for an impaired innate anti-HIV immune response. However, the presence of functionally-competent pDCs in slow progressors implies that the loss of pDCs early in infection may be critical to control of HIV infection through innate immune mechanisms, and may influence the progression of disease.

Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3+Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

“…Meera et al noted an increased frequency of blood pDCs undergoing apoptosis directly ex vivo in individuals with early and advanced HIV infection (69). The lack of similar observations of decreased survival tendencies of blood pDCs based on Bcl-2 and caspase-3 expression in our study may reflect analysis of different cohorts of HIV-1-infected donors in addition to differences in the assays used to detect apoptosis.…”

“…In a recent study using direct ex vivo annexin V and 7-AAD staining to evaluate apoptosis of blood mDCs, Meera et al reported a higher percentage of apoptotic mDCs in AIDS patients compared to controls (69). Although we also observed HIV-associated, proapoptotic changes in Bcl-2 and caspase-3 expression in blood mDCs directly ex vivo, we did not observe HIV-associated significant increases in DCs undergoing apoptosis using annexin V/7-AAD staining on cultured PBMC.…”

DCs and NK cells: critical effectors in the immune response to HIV-1

“…Aberrant IFNα production during HIV infection may impede the differentiation of cDCs from monocytes 33 or other precursors. Also, DCs from patients with HIV show increased apoptosis compared with DCs from uninfected individuals 34 .…”

“…Consistent with this, activation markers are upregulated by blood pDCs during acute HIV infection, suggesting that these pDCs have responded to virus in vivo . Furthermore, IFN-producing pDCs accumulate in draining lymph nodes of HIV patients 35–36 , although these pDCs are prone to apoptosis 34, 36 . Nonetheless, evidence is emerging that pDCs have a crucial role in the immune dysregulation that leads to the development of AIDS.…”

Current Status of Research on HIV Epidemic, Pathogenesis, Management and Prevention in India

“…Two studies published from India shed some light on the role of dendritic cells (DC) in HIV infection. Both studies have shown that the plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDCs) were significantly reduced in HIV infection and correlated negatively with plasma viral load [41,42]. Singh et al have shown that there is irreversible loss of pDCs in early HIV infection and in AIDS stage.…”