Persistent Abnormalities in Peripheral Blood Dendritic Cells and Monocytes from HIV-1-Positive Patients After 1 Year of Antiretroviral Therapy

Abstract

Antiretroviral therapy (ART) has led to marked decreases in morbidity and mortality rates among HIV-1-positive patients; however, immune recovery is not complete. Although dendritic cells (DCs) were shown to be involved in HIV-1 pathogenesis, few studies have investigated the effect of ART on DCs. We have analyzed the effect of ART on numerical distribution, expression of chemokine receptors, and ex vivo production of inflammatory cytokines by peripheral blood (PB) monocytes and DCs in a cohort of chronically infected HIV-1-positive patients. Patients were tested before therapy and at weeks +2, +4, +8, +12, and +52 after starting ART.Our results show an incomplete T-cell immune reconstitution in chronically infected patients who had undetectable plasma viremia while taking ART for 1 year. This was associated with persistent abnormalities at week +52 of ART, corresponding to increased numbers of CD16 DCs and monocytes, as well as altered expression of CXC chemokine receptors, in the form of increased CXCR1 expression on monocytes and decreased reactivity for CXCR2 and/or CXCR4 on myeloid and plasmacytoid DCs. In addition, an abnormally high spontaneous ex vivo secretion of inflammatory cytokines by CD16 DCs and monocytes was still detected after 1 year of ART. These abnormalities were especially pronounced in patients with less than 200 CD4 T cells/microL, which could be related to the persistence of undetected viral replication and sustained immune activation.

Evidence of dysregulation of dendritic cells in primary HIV infection

“…Bacterial translocation that results from massive CD4 ϩ T-cell depletion in gut lymphoid tissue by HIV may result in elevated levels of bacterial products containing lipopolysaccharides and CpGs that could activate innate immune cells, including DCs, 43 through binding of TLRs to induce the production of proinflammatory cytokines/chemokines. Consistent with these hypotheses, we (data not shown) and others 28,34,44 have observed slightly up-regulated levels of CD40 and/or CD86 on, as well as the spontaneous production of cytokines/chemokines 30,45 by circulating DC subsets from HIV-infected subjects. IFN␣ has been shown to up-regulate the expression of TLRs in macrophages 46 ; and PBMCs from chronically HIV-infected subjects have increased expression of TLRs.…”

Relationship between CD38 expression on peripheral blood T‐cells and monocytes, and response to antiretroviral therapy: A one‐year longitudinal study of a cohort of chronically infected ART‐naive HIV‐1+ patients

“…Altogether, these findings would support the notion that residual HIV-1 replication persists in reservoirs such as lymphoid tissues (21,22,25), which could induce a quantitative increased anti-HIV-1 cytotoxic immune response due to partial recovery of the immune surveillance and persistence of the virus. Accordingly, a strong association between the mean amount of CD38 molecules expressed per CD8þ T-cell and the frequency of HIV-1-specific CD8þ cytotoxic T-lymphocytes has recently been reported in untreated patients (48), and we have observed an increased production of inflammatory cytokines by PB monocytes and CD16þ DC in HIV-1þ patients at advanced stages of the disease with undetectable plasma viral load, even after one year of ART (49). Moreover, in the present study an altered long-term reconstitution of PB T-cell counts was observed, with the absolute number of PB CD4þ T-cells remaining abnormally low while that of CD8þ T-lymphocytes was significantly increased after one year of ART in both groups of HIV-1þ patients.…”

APOBEC3G upregulation by alpha interferon restricts human immunodeficiency virus type 1 infection in human peripheral plasmacytoid dendritic cells

“…Furthermore, the decrease in pDCs is consistent with the fact that CD4 T-cells and IFN-a production are profoundly and transiently impaired in primary HIV-1 infection (Kamga et al, 2005;Killian et al, 2006). In fact, the pDC population and consequent IFN-a secretion remain low even after 1 year of suppressive highly active antiretroviral therapy (HAART) possibly due to residual replication of HIV-1 and sustained immune activation (Almeida et al, 2006). Because pDCs are susceptible to HIV-1 infection, it is important to explore antiviral mechanisms that protect pDCs from this infection.…”