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


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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    • "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). "

    Understanding HIV/AIDS Management and Care - Pandemic Approaches in the 21st Century, 12/2011; , ISBN: 978-953-307-603-4
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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.
    PLoS ONE 04/2011; 6(4):e19352. DOI:10.1371/journal.pone.0019352 · 3.23 Impact Factor
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    • "Renal glomerular and tubular epithelial cells have been shown to harbor both HIV DNA and mRNA, suggesting productive infection. 87,88 Circularized viral DNA has also been found in kidney biopsies suggesting active replication in renal tissue, although infiltrating infected leukocytes harbor more viral mRNA than renal epithelium.87 Productive HIV infection in renal epithelial cells was recently confirmed by in situ hybridization polymerase chain reaction (PCR), and phylogenetic analyses of kidney-derived sequences conducted in the same study revealed evidence of tissue-specific evolution when compared to those of peripheral blood mononuclear cells.88 "
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    ABSTRACT: Even though the treatment of human immunodeficiency virus (HIV)-infected individuals with highly active antiretroviral therapy (HAART) provides a complete control of plasma viremia to below detectable levels (<40 copies/mL plasma), there is an unequal distribution of all antiretroviral drugs across diverse cellular and anatomic compartments in vivo. The main consequence of this is the acquisition of resistance by HIV to all known classes of currently prescribed antiretroviral drugs and the establishment of HIV reservoirs in vivo. HIV has a distinct advantage of surviving in the host via both pre-and postintegration latency. The postintegration latency is caused by inert and metabolically inactive provirus, which cannot be accessed either by the immune system or the therapeutics. This integrated provirus provides HIV with a safe haven in the host where it is incessantly challenged by its immune selection pressure and also by HAART. Thus, the provirus is one of the strategies for viral concealment in the host and the provirus can be rekindled, through unknown stimuli, to create progeny for productive infection of the host. Thus, the reservoir establishment remains the biggest impediment to HIV eradication from the host. This review provides an overview of HIV reservoir sites and discusses both the virtues and problems associated with therapies/strategies targeting these reservoir sites in vivo.
    HIV/AIDS - Research and Palliative Care 06/2010; 2:103-22.
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