Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1

Abstract

Recently it has been shown that the 2 populations of blood dendritic cells (DCs), termed plasmacytoid (pcDCs) and myeloid (myDCs), are reduced in HIV-1 infection. This study aimed to determine whether these 2 populations are targets for HIV-1 infection and whether their ability to stimulate T-lymphocyte proliferation is affected. Highly purified populations of myDCs and pcDCs were isolated from the blood of antiretroviral treatmentnaive patients and assessed for the level of HIV provirus by polymerase chain reaction (PCR). We show that both populations are targets for HIV-1 infection as indicated by the presence of provirus in 12 of 14 pcDC and 13 of 14 myDC samples tested. A proportion of this provirus is integrated in myDCs. The ability of both myDCs and pcDCs from HIV-1-infected patients to stimulate allogeneic T-lymphocyte proliferation in a 6-day mixed leukocyte reaction was severely impaired, IntroductionPrimary adaptive immune responses are initiated by dendritic cells (DCs) through the presentation of antigen to T lymphocytes. DCs are also important stimulators of innate immune responses. 1,2 DCs constitute about 1% of the mononuclear cell population of blood and can be divided into 2 major subpopulations that are phenotypically and functionally distinct. 3,4 Myeloid DCs (myDCs) express CD11c, CD13, CD33, and the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) and secrete interleukin 12 (IL-12). They are precursors of classical antigen-presenting cells, including Langerhans cells and dermal and interstitial DCs. 5 By contrast, plasmacytoid DCs (pcDCs) are CD11c Ϫ ; lack myeloid markers but express CD68, CD36, IL-3 receptor-␣ (IL-3R␣), immunoglobulin-like transcript 3 (ILT3); and produce high amounts of interferon-␣ (IFN-␣), 6,7 a potent inhibitor of HIV-1 replication. 8 Unlike myDCs, which migrate to the tissues and intercept invading pathogens before migrating to the lymph nodes, pcDCs migrate directly from blood to the secondary lymphoid tissue where they differentiate into cells originally termed plasmacytoid T cells on the basis of their extensive endoplasmic reticulum. 9,10 It has long been known that during HIV-1 infection there is a progressive decline in CD4 T-lymphocyte numbers, and in the later stages of disease there is loss of HIV-specific cytotoxic Tlymphocyte activity. 11 Recently, we and others have reported that there is also a progressive loss in the number of blood DCs. [12][13][14][15] However, to fully understand the role of DCs in the pathogenesis of HIV-1, it is important to determine whether the 2 DC populations are targets for HIV-1 infection and whether their ability to stimulate T lymphocytes in infected individuals is affected. Evidence of infection would be important as it would provide a mechanism to explain DC loss and might facilitate infection of T lymphocytes during antigen presentation. Down-regulation of T-lymphocyte stimulatory capacity together with reduced numbers would severely suppress cell-mediated immunity and contribute to the immunosuppr...

Dendritic cell based vaccines for HIV infection

“…However, although it is true that viral escape to CTL has been extensively demonstrated, [30][31][32][33] some data suggest that the antigen-presenting functions of dendritic cells are impaired in HIV-1 infected patients and this could contribute to the functional defects of HIV-1-specific helper and CTL responses. 34,35 We think that our model could help to know if a correct antigen presentation with this therapeutic vaccine could reverse the functional defect of helper and CTL responses and prevent, at least partially, the viral escape.…”

Assessment of HIV infection in cells of infected individuals

“…As a direct consequence, the HIV codon usage dramatically from that of cellular genes [DONAGHY et al, 2003] .…”

“…On the other hand, accessory genes are expressed in vivo and increasing data indicate that they play important roles in the virus-host interplay [DONAGHY et al, 2003] . …”

“…From a virological point of view, the remarkably fast rate of HIV replication, and the enormous ability of this virus to modify in response to exogenous (pharmacologic) and endogenous (immune system) selective pressure, is underlined by the observation that a wildtype, drug-susceptible HIV strain can be totally replaced by a mutant, drugresistant strain within 2 ± 4 weeks after initiation of antiretroviral therapy [DONAGHY et al, 2003] .…”

Células dendríticas especializadas en presentación de antígenos exógenos a linfocitos T citotóxicos

“…Existe una subpoblación de CD que circula en la sangre y está presente en ór-ganos linfáticos denominada CD plasmocitoide. Su rasgo funcional más llamativo es que producen grandes cantidades de las proteínas antivirales INF-α e IFN-β en respuesta a la presencia de virus [42][43][44] . Las CD plasmocitoides detectan la presencia de RNA de características virales en sus endosomas a través del receptor TLR-7 [45][46][47] .…”