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Marras D, Bruggeman LA, Gao F, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy

Division of Nephrology, Department of Medicien, Mount Sinai School of Medicine, New York, New York, USA.
Nature Medicine (Impact Factor: 27.36). 06/2002; 8(5):522-6. DOI: 10.1038/nm0502-522
Source: PubMed

ABSTRACT

HIV-associated nephropathy is a clinicopathologic entity that includes proteinuria, focal segmental glomerulosclerosis often of the collapsing variant, and microcystic tubulointerstitial disease. Increasing evidence supports a role for HIV-1 infection of renal epithelium in the pathogenesis of HIV-associated nephropathy. Using in situ hybridization, we previously demonstrated HIV-1 gag and nef mRNA in renal epithelial cells of patients with HIV-associated nephropathy. Here, to investigate whether renal epithelial cells were productively infected by HIV-1, we examined renal tissue for the presence of HIV-1 DNA and mRNA by in situ hybridization and PCR, and we molecularly characterized the HIV-1 quasispecies in the renal compartment. Infected renal epithelial cells were removed by laser-capture microdissection from biopsies of two patients, DNA was extracted, and HIV-1 V3-loop or gp120-envelope sequences were amplified from individually dissected cells by nested PCR. Phylogenetic analysis of kidney-derived sequences as well as corresponding sequences from peripheral blood mononuclear cells of the same patients revealed evidence of tissue-specific viral evolution. In phylogenetic trees constructed from V3 and gp120 sequences, kidney-derived sequences formed tissue-specific subclusters within the radiation of blood mononuclear cell-derived viral sequences from both patients. These data, along with the detection of HIV-1-specific proviral DNA and mRNA in tubular epithelium cells, argue strongly for localized replication of HIV-1 in the kidney and the existence of a renal viral reservoir.

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Available from: Paul E Klotman, Sep 17, 2014
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    • "Renal biopsy data suggest that HIV-associated nephropathy (HIVAN) is the outcome of HIV-1 infection of kidney cells (Bruggeman and Nelson, 2009; Marras et al., 2002; Mikulak et al., 2010). However, kidney cells do not carry conventional HIV-1 receptors (Eitner et al., 2000); therefore, the route of HIV-1 entry into renal cell was not clear for a long time (Marras et al., 2002). Recently, enodocytic pathway for HIV-1 entry has been demonstrated to be an important mode of infection in several cells (Dezzutti et al., 2001; Li et al., 2007; Meng et al., 2003; Vidricaire et al., 2003). "
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    ABSTRACT: We hypothesized that HIV-1 may enter tubular cells by phagocytosis of apoptotic fragments of HIV-1-infected T cells infiltrating tubular interstitium. The study was designed to evaluate the interaction of programmed death-1 (PD-1) receptors on CD4 T cells and programmed death ligand-1 (PD-L1) on tubular cells (HK2 and HRPTEC, primary tubular cells). Co-cultivation of HIV-1 infected lymphocytes (HIV-LY) with HK2s/HRPTECs resulted in T cell apoptosis, uptake of the apoptosed HIV-LY by HK2s/HRPTECs, tubular cell activation and HIV expression. Cytochalasin-B inhibited tubular cell HIV-LY uptake and anti-PD-L1 antibody inhibited HIV-LY apoptosis and tubular cell HIV-LY uptake, activation and HIV expression. These observations do indicate induction of apoptosis of T cells due to interaction of PD-1 and PD-L1 upon co-cultivation and subsequent phygocytosis of HIV-laden apoptotic bodies by tubular cells and thus the transfer of HIV-1 into tubular cells. These findings identify a novel pathway that facilitates HIV-1 entry into tubular cell.
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    • "This is because there are many instances of HIV-1 infection where either the primary and/or co-receptors are missing from the infected cell. Indeed, HIV-1-infected CD4 negative -cells have been identified in vivo, including various brain cells (Pumarola-Sune et al., 1987, Ward et al., 1987, Wiley et al., 1986)epithelial cells (Nelson et al., 1988), cardiomyocytes (Barbaro et al., 1998), CD4 negative -lymphocytes (Livingstone et al., 1996, Saha et al., 2001a), renal tubular epithelial cells(Marras et al., 2002, Wyatt & Klotman, 2007), hepatocytes (Fromentin et al., 2011) and thymocytes (Kitchen et al., 1997). HIV-1 has also been shown to infect CD4-negative neural and epithelial cells in vitro, although not productively (Clapham et al., 1989, Tateno et al., 1989). "

    Full-text · Chapter · Dec 2011
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    • "Gp120 coreceptor binding sites of CD4-independent HIV-1 variants are exposed before the CD4 binding, and the CD4-independent gp120 directly interacts with the coreceptor for the entry [5]. It has been reported that CD4-negative cells such as liver, kidney, and CD8+ T cells are infected with the CD4-independent HIV-1 in AIDS patients, and such CD4-independent variants are thought to be associated with hepatitis, nephropathy, and CD8+ T cell dysfunction in AIDS patients [6], [8], [9], [10]. Almost all simple retroviruses, including murine leukemia viruses (MLVs), recognize multiple membrane-spanning proteins as the HIV-1 coreceptors. "
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    ABSTRACT: During a comparison of the infectivity of mNDK, a CD4-independent human immunodeficiency virus type 1 (HIV-1) strain, to various cell lines, we found that HeLa cells were much less susceptible than 293T and TE671 cells. Hybridoma cells between HeLa and 293T cells were as susceptible as 293T cells, suggesting that cellular factors enhance the mNDK infection in 293T cells. By screening a cDNA expression library in HeLa cells, cystatin C was isolated as an enhancer of the mNDK infection. Because cathepsin B protease, a natural ligand of cystatin C, was upregulated in HeLa cells, we speculated that the high levels of cathepsin B activities were inhibitory to the CD4-independent infection and that cystatin C enhanced the infection by impairing the excessive cathepsin B activity. Consistent with this idea, pretreatment of HeLa cells with 125 µM of CA-074Me, a cathepsin B inhibitor, resulted in an 8-fold enhancement of the mNDK infectivity. Because cathepsin B is activated by low pH in acidic endosomes, we further examined the potential roles of endosomes in the CD4-independent infection. Suppression of endosome acidification or endocytosis by inhibitors or by an Eps15 dominant negative mutant reduced the infectivity of mNDK in which CD4-dependent infections were not significantly impaired. Taken together, these results suggest that endocytosis, endosomal acidification, and cathepsin B activity are involved in the CD4-independent entry of HIV-1.
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