HIV-1 infects CD4+ cells via interaction with CD4 and either CCR5 or CXCR4. However, only CCR5-using (R5) viruses are efficiently transmitted and sustain the viral pandemics, while CXCR4-using (X4) viruses emerge later in coincidence with the immunodeficiency state and progression to AIDS in about 50% of individuals infected with subtype B HIV-1, but not with other subtypes. Unraveling cellular and molecular correlates of this asymmetric co-receptor use would be relevant to understand HIV pathogenesis as well as for the development of preventive strategies aimed at blocking R5 HIV-1 spreading. We have previously reported that cord blood derived CD4+T cells (CB4 cells) maintained in a sub-optimally activated state in IL-2 enriched medium for 7-14 days before infection are permissive for R5 and restricted for X4 HIV-1 replication. Of interest, this restriction did not occur at the level of viral entry, but it was rather correlated to a superior capacity of R5 HIV-1 to spread after infection [1]. In the present study, we examined the transcriptomic profile at different time points (8, 24, 48, 72 h) of CB4 cells established from 6 independent donor/infection pairs after infection with isogenic NL4-3 (X4) and NL-AD8 (R5) viruses normalized for MOI. Gene expression was measured using Human Genome U95A chips and analyzed with the DAVID knowledge base software. Approximately 900 and 1,100 genes were selectively mobilized by R5 and X4 HIV-1 infection, respectively, vs. mock-stimulated uninfected control cells. An additional 420 genes were modulated by both viruses vs. controls. R5 HIV-1 induced a rapid mobilization of genes linked to cell proliferation and signal transduction, whereas the X4 virus predominantly modulated the expression of genes associated with cell death and the immune response. Both viruses upregulated the expression of CXCL12/SDF-1α, but only X4 downregulated CXCR4 mRNA; CCR5 mRNA was unaffected by either infection at all time points. Other genes previously linked to control of HIV replication that were modulated by R5 and X4 HIV-1 include APOBEC-3G, IFN-γ, CCL5/RANTES, CCL7/MCP-3 and CCL14/HCC1. We are currently analyzing additional genes discordantly co-modulated by R5 and X4 viruses in the search of host genes associated with the permissive vs. restricted HIV replicative profile in this model system. Thus, both R5 and X4 HIV-1 profoundly affect the transcriptional activity of primary CD4+T lymphocytes even in the absence of overt replication (as observed in X4 infection).
Interleukin-2 (IL-2) increases circulating CD4(+) lymphocytes in patients infected with human immunodeficiency virus-1. We studied Epstein-Barr virus (EBV) dynamics in 40 patients treated with antiretroviral therapy (ART) plus different IL-2 regimens. EBV-DNA tended to increase in both peripheral blood cells and plasma after continous infusion followed by intermittent subcutaneous high-dose IL-2, while EBV-DNA decreased in cells (p=0.0078) and disappeared in plasma after intermittent subcutaneous low-dose IL-2. Over 12 months, the dynamics of EBV differed between the two groups both in cells (p=0.0184) and plasma (p=0.0114). Thus, as a function of dose, IL-2 therapy may significantly affect the dynamics of EBV infection.
K-feldspar megacrysts (Kfm) are used to investigate the magmatic evolution of the 7 Ma Monte Capanne (MC) monzogranite (Elba, Italy). Dissolution and regrowth of Kfm during magma mixing or mingling events produce indented resorption surfaces associated with high Ba contents. Diffusion calculations demonstrate that Kfm chemical zoning is primary. Core-to-rim variations in Ba, Rb, Sr, Li and P support magma mixing (i.e. high Ba and P and low Rb/Sr at rims), but more complex variations require other mechanisms. In particular, we show that disequilibrium growth (related to variations in diffusion rates in the melt) may have occurred as a result of thermal disturbance following influx of mafic magma in the magma chamber. Initial 87Sr/86Sr ratios (ISr) (obtained by microdrilling) decrease from core to rim. Inner core analyses define a mixing trend extending towards a high ISr–Rb/Sr melt component, whereas the outer cores and rims display a more restricted range of ISr, but a larger range of Rb/Sr. Lower ISr at the rim of one megacryst suggests mixing with high-K calc-alkaline mantle-derived volcanics of similar age on Capraia. Trace element and isotopic profiles suggest (1) early megacryst growth in magmas contaminated by crust and refreshed by high ISr silicic melts (as seen in the inner cores) and (2) later recharge with mafic magmas (as seen in the outer cores) followed by (3) crystal fractionation, with possible interaction with hydrothermal fluids (as seen in the rim). The model is compatible with the field occurrence of mafic enclaves and xenoliths.
We have investigated monocyte function in 17 intravenous drug abusers with the clinical and laboratory features of lymphadenopathy syndrome (LAS). LAS patients had normal numbers of circulating monocytes. Monocytes from LAS patients were comparable to cells from normal donors in terms of phagocytosis of latex beads, interleukin-1 secretion, O2- release and killing of antibody-sensitized lymphoma cells or actinomycin D pretreated WEHI 164 cells. In contrast 13 out of 17 LAS subjects tested in this respect as well as six out of nine AIDS patients showed a marked defect of monocyte chemotaxis. Thus monocytes from patients with LAS or AIDS have a selective defect of monocyte chemotaxis.
