Irreversible loss of pDCs by apoptosis during early HIV infection may be a critical determinant of immune dysfunction.

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.