Infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5). Homozygosity for a 32-bp deletion in the CCR5 allele provides resistance against HIV-1 acquisition. We transplanted stem cells from a donor who was homozygous for CCR5 delta32 in a patient with acute myeloid leukemia and HIV-1 infection. The patient remained without viral rebound 20 months after transplantation and discontinuation of antiretroviral therapy. This outcome demonstrates the critical role CCR5 plays in maintaining HIV-1 infection.

HIV entry into CD4 ؉ cells requires interaction with a cellular receptor, generally either CCR5 or CXCR4. We have previously reported the case of an HIV-infected patient in whom viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with CCR5⌬32/⌬32 stem cells. However, it was expected that the long-lived viral reservoir would lead to HIV rebound and disease progression during the process of immune reconstitution. In the present study, we demonstrate successful reconstitution of CD4 ؉ T cells at the systemic level as well as in the gut mucosal immune system after CCR5⌬32/⌬32 stem cell transplantation, while the patient remains without any sign of HIV infection. This was observed although recovered CD4 ؉ T cells contain a high proportion of activated memory CD4 ؉ T cells, ie, the preferential targets of HIV, and are suscep- IntroductionDestruction of the immune system by the HIV is driven by the loss of CD4 ϩ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4 ϩ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. 1 Because subsequent viral replication requires cellular gene expression processes, activated CD4 ϩ cells are the primary targets of productive HIV infection. Consequently, HIV infection leads predominantly to the depletion of activated memory CD4 ϩ T cells, most of which reside in the gastrointestinal (GI) mucosa. [2][3][4] Although therapeutic control of HIV replication allows the immune system to partially restore and delays disease progression, the cure of HIV infection remains still unachievable with use of the currently available antiretroviral drugs. The major barrier to viral eradication in patients receiving antiretroviral therapy (ART) is the establishment of HIV reservoirs, including low-level productively and latently infected cells. [5][6][7] Thus, maintenance of replicationcompetent HIV in long-lived cells and distinct anatomical sanctuaries allows the virus to reseed the body once ART is discontinued. 8 Cells of persons homozygous for the CCR5 gene variant ⌬32 (CCR5⌬32/⌬32) are naturally resistant to infection with CCR5-tropic HIV strains (R5 HIV) because of the lack of CCR5 cell-surface expression. 9 Previously, we demonstrated the feasibility of hematopoietic stem cell transplantation (SCT) with CCR5⌬32/ ⌬32 donor cells (CCR5⌬32/⌬32 SCT) in an HIV-infected patient with relapsed acute myeloid leukemia (AML) and documented absent viremia during the first 20 months of remission, during which time the patient did not receive ART. 10,11 This case clearly emphasizes the importance for continuing research in the field of CCR5-targeted treatment strategies, but uncertainty has remained over whether a cure for HIV infection has been achieved in this patient.In the setting of HIV infection, the effects of pretransplantation conditioning do not allow the complete elimination of HIV, as demonstrated by previous studies in which researchers demonstrated that HIV...

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Background: Giardia lamblia causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. Aim: To characterise the inherent pathomechanisms of G lamblia infection. Methods: Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I SC ) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. Results: In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) V cm 2 ; p,0.05) whereas mannitol flux was not significantly altered (140 (27) vs 105 (16) nmol/h/cm 2 ). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I SC increased from 191 (20) in control to 261 (12) mA/h/cm 2 in giardiasis. The bumetanide-sensitive portion of I SC in giardiasis was also increased (51 (5) vs 20 (9) mA/h/cm 2 in control; p,0.05). Finally, phlorizin-sensitive Na + -glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) mA/h/cm 2 ). Conclusions: G lamblia infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na + -dependent D-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components.

Recent evidence indicates that regulatory T cells (T(regs)) play an important role in HIV infection. However, although the gastrointestinal mucosa is a key compartment in HIV disease, no data on mucosal T(regs) in HIV infection are available. In this study, we compared the frequency of T(regs) in duodenal mucosa and peripheral blood (PB) of 13 treatment-naive and 13 suppressively treated HIV-infected patients with that of 6 patients with norovirus infection and 12 healthy controls. T(regs) were quantified by immunohistochemistry (CD3/FOXP3) and further characterized (CD25, CTLA-4, GITR) by immunohistochemistry, immunofluorescence, and fluorescence-activated cell sorting (FACS). Both the frequency and the absolute count of mucosal T(regs) were highly increased in untreated HIV patients but were normal in treated HIV patients. In contrast, in peripheral blood of HIV patients, the absolute number of T(regs) was not increased, and their frequency was only slightly elevated. In norovirus infection, frequency of mucosal T(regs) in the CD4+ T-cell subset was not elevated. The high increase in count and frequency of mucosal T(regs) seems to be a characteristic feature of untreated HIV infection, suggesting a significant contribution of T(regs) to the pathogenesis of HIV disease. Their role may be 2-edged: attenuating HIV-induced immune hyperactivation while suppressing the immune response to HIV and mucosal pathogens.

Epidemiologic trends of human leptospirosis in Germany were investigated by analyzing national surveillance data from 1962 to 2003 and by conducting a questionnaire-based survey from 1997 to 2000. After a steady decrease of leptospirosis incidence from 1962 to 1997, surveillance data indicate an increase in disease incidence to 0.06 per 100,000 (1998–2003). Of 102 laboratory-confirmed cases in humans from 1997 to 2000, 30% were related to occupational exposures. Recreational exposures were reported in 30% (including traveling abroad in 16%), whereas residential exposure accounted for 37% of the cases. Direct contact with animals, mostly rats and dogs, was observed in 31% of the cases. We conclude that recent changes in transmission patterns of leptospirosis, partially caused by an expanding rat population and the resurgence of canine leptospirosis, may facilitate the spread of the disease in temperate countries like Germany. Preventive measures should be adapted to the changing epidemiology of leptospirosis.