Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-α but Not Proinflammatory Cytokines

Abstract

We analyzed reconstitution characteristics of plasmacytoid dendritic cells (PDCs) and myeloid DCs-1 in 38 HIV-1-infected patients with impaired restoration of CD4 T cell counts despite prolonged suppression of plasma viremia (discordant) and compared them with 42 patients showing good immunological and virological responses following highly active antiretroviral therapy (HAART). While myeloid DCs showed spontaneous recovery following HAART in both the groups, the discordant patients demonstrated poor peripheral reconstitution of PDCs as compared with concordant patients. The ability of PDCs to produce IFN-α following stimulation with TLR7 ligand imiquimod and TLR9 ligand CpG ODN-2216 was also impaired in discordant patients even after 2 years following initiation of HAART. Lower IFN-α expression in the PDCs following TLR stimulation was further associated with lower expression of transcription factor, IFN regulatory factor-7. In contrast, production of TNF-α and IL-6 following TLR stimulation was comparable in both groups of patients, indicating that impaired reconstitution characteristics do not affect the capacity of PDCs to produce proinflammatory cytokines. The discordant patients had significantly lower baseline CD4 T cell counts and higher baseline viral load at the initiation of HAART implying that lower baseline CD4 T cell counts and higher plasma viral load are associated with impaired restoration of CD4 T cells and PDCs, thus, increasing the susceptibility of discordant patients toward opportunistic infections despite virological control.

Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages

“…[39][40][41] However, their numbers and ability to produce type I IFNs are significantly reduced by HIV infection. [42][43][44][45][46] Thus, an IFNmediated antiviral response mounted by nonimmune cells such as brain ECs is likely to be beneficial for CNS protection. Although two early studies reported that brain ECs could be infected with HIV, 3,47 our results showed that hCMEC/D3 cells were not susceptible to HIV infection (supplemental Figure 5), which is consistent with the majority of evidence.…”

Prevalence of discordant immunologic and virologic responses in patients with AIDS under antiretroviral therapy in a specialized care center in Brazil

“…While some researchers have hypothesized that it could be the consequence of impaired thymic function 33,38 , others considered the possibility of an association with genetic factors 31 . SACHDEVA et al 34 reported a limited capacity for a-interferon production in patients with PIR. Down-regulation of interleukin-7 (IL-7) has also been associated with discordant immunologic and virologic responses [3][4][5] , and an increase in absolute CD4 cell count was observed in patients experimentally treated with IL-7 in a phase I/IIa study 20 .…”

“…There are numerous different conclusions about the relevance of possible risk factors, such as advanced age at the beginning of ART 9,11,13,15,18,19,24,28,30,41 , low initial values of CD4 cell count 8,9,17,18,22,25,34,35 , high initial values of CD4 cell count 2,7,9,10,24,28,36,41 , low nadir CD4 cell count 9 , ART regimen 24,42 , different levels of initial viral load 10,14,18,19,24,28,30,34,41 , the presence of associated conditions 12,34 and even category of exposure to HIV 14,19,28 .…”

Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness

“…The suggest, in agreement with previous studies, that the expression of TLR9-induced IFN-α is affected by loss of pDCs numbers as well as a functional defect of pDCs. 11,[34][35][36] Taken together, our results suggest that, in addition to viral rebound and decline in CD4 + T cells, TI also contributes to dysregulation of innate immunity, including fluctuation of DC subsets and defective or hyperactivated TLR responsiveness in HIV-1-infected individuals. Since differences in the viral and immunological parameters studied here were independent of vaccination regime, we chose to consider all study subjects as one group.…”