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The aim of the present study was to investigate the possible role of human immunodeficiency virus (HIV) infection in the natural course of chronic hepatitis C. Seventy-six adult patients with chronic parenterally acquired hepatitis C virus (HCV) infection examined from 1989 to 1993 were enrolled; of these 32 (42.1%) were HIV positive and 44 (57.9%) were HIV negative. Serum HCV RNA quantitation was carried out by polymerase chain reaction in a well-characterized group (n = 20; 11 HIV positive and 9 HIV negative). Distribution of histological findings in liver biopsies from both HIV-infected and noninfected patients was similar. However, within 15 years after initial HCV infection, 8 of 32 (25%) HIV-positive patients developed cirrhosis, in comparison with only 2 of 31 (6.5%) patients in the HIV-negative group (p < 0.05); similar incidences of cirrhosis were found in both patient groups within 5 and 10 years after HCV infection. Most of the HIV-negative cirrhotic patients (9 of 11) developed cirrhosis in a time interval longer than 15 years. Finally, HCV load was almost ten times higher (1 10-fold dilution) in the HIV-positive group, but this difference did not reach statistical significance in this small study population. These results suggest that HIV infection can alter the natural course of chronic parenterally acquired hepatitis C, causing an unusually rapid progression to cirrhosis.

The myeloid C-type lectin dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN, CD209) recognizes oligosaccharide ligands on clinically relevant pathogens (HIV, Mycobacterium, and Aspergillus). Alternative splicing and genomic polymorphism generate DC-SIGN mRNA variants, which have been detected at sites of pathogen entrance and transmission. We present evidence that DC-SIGN neck variants are expressed on dendritic and myeloid cells at the RNA and protein levels. Structural analysis revealed that multimerization of DC-SIGN within a cellular context depends on the lectin domain and the number and arrangement of the repeats within the neck region, whose glycosylation negatively affects oligomer formation. Naturally occurring DC-SIGN neck variants differ in multimerization competence in the cell membrane, exhibit altered sugar binding ability, and retain pathogen-interacting capacity, implying that pathogen-induced cluster formation predominates over the basal multimerization capability. Analysis of DC-SIGN neck polymorphisms indicated that the number of allelic variants is higher than previously thought and that multimerization of the prototypic molecule is modulated in the presence of allelic variants with a different neck structure. Our results demonstrate that the presence of allelic variants or a high level of expression of neck domain splicing isoforms might influence the presence and stability of DC-SIGN multimers on the cell surface, thus providing a molecular explanation for the correlation between DC-SIGN polymorphisms and altered susceptibility to HIV-1 and other pathogens. Dendritic cells (DCs)4 link the innate and adaptive branches of the immune response by virtue of their capacity to recognize pathogen-specific structures (1) via pathogen-associated molecular pattern receptors (2). Immature DCs express a number of lectins and lectin-like molecules, which endow them with a broad capacity for pathogen recognition, as they mediate the specific recognition of parasitic, bacterial, yeast, and viral pathogens (3, 4). Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209) is a type II membrane C-type lectin (5, 6) abundantly expressed in vivo on myeloid DC and macrophage subpopulations (5-12), as well as on in vitro generated monocyte-derived dendritic cells (MDDCs) and alternatively activated macrophages (12-14). DC-SIGN binds a large array of pathogens, including HIV (15), Ebola (16), hepatitis C (17-19), and Dengue virus (20) and Leishmania amastigotes and promastigotes (21, 22), Mycobacterium tuberculosis (23, 24), Aspergillus fumigatus (25), and Candida albicans (26) via mannan-and Lewis oligosaccharides-dependent interactions (27,28). In addition, DC-SIGN appears to mediate DC contacts with naïve T lymphocytes through its recognition of ICAM-3 (6), DC trafficking through interactions with endothelial ICAM-2 (8), and DC-neutrophil interactions by interacting with the CD11b/CD18 integrin (29).Structurally, DC-SIGN contains a carbohydrate-recognition domain, a neck region composed of...

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To define the role of sexual transmission in the spread of hepatitis C virus (HCV) infection, a seroprevalence study of antibodies against HCV was performed in populations at high risk for sexually transmitted diseases. Subjects included 310 female prostitutes, 88 clients of prostitutes, 168 homosexual men and 147 stable heterosexual partners of index cases reactive for anti-HCV (98 of whom were partners of drug addicts coinfected with HCV and human immunodeficiency virus [HIV]). All subjects denied prior transfusion or intravenous drug use. Controls were 400 voluntary blood donors selected randomly from first-time donors. The prevalence of anti-HCV by enzyme immunoassay, confirmed by a second-generation recombinant immunoblot assay, was 6.4% in prostitutes, 6.8% in clients of prostitutes, 4.2% in homosexual men, 7.4% in heterosexual partners of index cases and 1.2% in random donors. However, the anti-HCV prevalence in stable heterosexual partners of HCV-positive/HIV-positive index cases was 2.2 times higher than in stable heterosexual partners of index cases reactive for anti-HCV only (9.2% vs. 4.1%), and sexual partners of index cases coinfected with HCV and HIV were almost three times more likely to be infected with HIV than with HCV (25.5% vs. 9.2%). These data suggest that HCV infection may be sexually transmitted but with low efficiency and that this efficiency could be increased in the presence of coexistent HIV infection in the index case.

The only clinically validated assay available to determine HIV tropism is Trofile, an assay that possesses some limitations. Our first aim was to develop a new phenotypic tropism test (TROCAI [tropism coreceptor assay information]) and to categorize results generated by this test according to the virological response to a short-term exposure to the CCR5 receptor antagonist maraviroc (maraviroc clinical test). Our second aim was to compare TROCAI results to those obtained by Trofile enhanced sensitivity (ES) and to different genotypic algorithms. TROCAI assayed HIV tropism in 33 HIV-infected patient viral isolates obtained from a modified coculture, followed by multiple infection cycles of indicator cells. TROCAI obtained a reportable result in all patients with viral loads of >500 HIV RNA copies/ml and in 3/6 patients with <500 HIV RNA copies/ml (30/33 patients, 91.9%). Patients who responded to maraviroc had an X4-using virus proportion in indicator cell supernatant of 0 to 0.41%. Hence, we used the threshold of 0.5% to categorize TROCAI results as R5 (<0.5%) or dual/mixed (>0.5%). The concordance between TROCAI and Trofile (ES) was 22/24 (91.6%), and with genotypic approaches it was 22/26 (84.6%). TROCAI results, which were categorized in this study by the maraviroc clinical test, could be used as a test in addition to those currently used to select patients for treatment with CCR5 antagonists.

The single-nucleotide polymorphism (SNP) rs12979860 near the IL28B gene has been associated with the spontaneous clearance of hepatitis C virus. We sought to determine whether this SNP could be associated with the spontaneous control of human immunodeficiency virus (HIV) infection. We studied the prevalence of the IL28B CC genotype among 53 white HIV controllers, compared with the prevalence among 389 HIV-infected noncontrollers. We found that the IL28B CC genotype was independently associated with spontaneous HIV control (odds ratio [OR], 2.669; P = .017), as were female sex (OR, 7.077; P ≤ .001) and the presence of HLA-B57 and/or B27 (OR, 3.080; P = .017). This result supports the idea that common host mechanisms are involved in the spontaneous control of these 2 chronic infections.