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Retrovial infection and kidney failure


Senior Member
Cell. 1990 Aug 10;62(3):425-34.

Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome.

Weiher H, Noda T, Gray DA, Sharpe AH, Jaenisch R. Whitehead Institute, Massachusetts Institute of Technology, Cambridge 02142.
Transgenic mouse strains carrying proviruses were generated by exposing mouse embryos to a recombinant retrovirus. Animals carrying a single provirus were intercrossed to derive mice homozygous for a given proviral insertion. Adult mice homozygous for the Mpv17 integration developed nephrotic syndrome and chronic renal failure. Histologically, affected kidneys showed progressive glomerular sclerosis. Similar lesions are seen in patients with progressive renal function deterioration. A probe to DNA sequences flanking the provirus detected a 1.7 kb RNA ubiquitously expressed during embryogenesis and in adults with high levels in kidney, brain, and heart. This RNA was not detected in tissues of homozygous animals, suggesting that the provirus interferes with RNA expression. Sequence analysis of the cDNA revealed that the gene encodes a 176 amino acid peptide containing hydrophobic regions, suggesting membrane association of the putative protein. The Mpv17 mutant is a potentially useful experimental system for studying mechanisms leading to renal disorders in man. PMID: 1696177

HIV-related kidney failure (from before the wide-spread use of antiretrovirals, ie the virus solely responsible)

Klin Wochenschr. 1989 Sep 1;67(17):889-94.

Acquired immunodeficiency syndrome (AIDS)--related renal disease.

Bourgoignie JJ. Department of Medicine, University of Miami School of Medicine, Florida.
More than 87,000 patients with acquired immunodeficiency syndrome (AIDS) were reported to the Centers for Disease Control in the United States, of whom more than half died through January 1989. When the AIDS epidemic is considered worldwide, these numbers should be doubled at least [27]. Whereas electrolyte disorders and acute renal complications were recognized early on in the AIDS epidemic, it was not until 1984 that a nephropathy was described in patients with human immunodeficiency virus-Type 1 (HIV-1) (formerly called LAV/HTLV-III) infection [18, 30, 36]. This nephropathy was characterized, clinically, by heavy proteinuria or the nephrotic syndrome and a rapid progression to end-stage chronic renal failure and, pathologically, by an aggressive form of focal segmental glomerulosclerosis. The existence of an AIDS-related nephropathy was not readily accepted because of its uneven geographic distribution amongst areas severely affected by the AIDS epidemic [24, 48]. This brief review summarizes the clinical and pathologic features of AIDS-related nephropathy. PMID: 2681968

Am J Nephrol. 1992;12(5):281-7.

Glomerular disease and human immunodeficiency virus infection in Brazil.

Lopes GS, Marques LP, Rioja LS, Basilio-de-Oliveira CA, Oliveira AV, Nery AC, Santos Oda R. Department of General Medicine, School of Medicine and Surgery, University of Rio de Janeiro, Brazil.
Clinically overt glomerular disease was detected in 6 (1.1%) of 543 patients with HIV infection followed at a Brazilian National Referral Center for AIDS. In 4 cases, glomerulosclerosis was present (focal and segmental in 3, diffuse and global in 1) and rapid progression to terminal renal failure was observed 1-10 months after clinical presentation. The other 2 patients died with normal renal function, and autopsy studies suggested the diagnosis of minimal change disease. Clinically overt glomerular disease was significantly more common among Black patients, whether all the cases with glomerulopathy (p < 0.001) or just the cases with glomerular sclerosis were considered (p = 0.011). Autopsy study of renal fragments from patients without clinical evidence of glomerular disease was additionally performed and revealed the presence of focal and segmental glomerulosclerosis in 3 cases (7.5%). We concluded that a glomerulopathy with clinicopathological features which match the definition of HIV nephropathy can be found among Brazilian patients with HIV infection. Accordingly to what has been described in American series, Brazilian Black patients seem to be at increased risk of the development of that nephropathy. PMID: 148899

this is intriguing considering that aggressive form prostate cancer is much more prevalent in black men ?

Semin Nephrol. 1998 Jul;18(4):373-7.

The human immunodeficiency virus (HIV) epidemic and HIV-associated nephropathy.

Winston JA, Burns GC, Klotman PE.Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), the single most common cause of end-stage renal failure in seropositive patients, has increased in incidence by 30% each year since 1991. Occurring almost exclusively in blacks, HIVAN became the third leading cause of ESRD in blacks, ages 20 to 64, in 1995. During that year, the absolute number of new acquired immune deficiency syndrome (AIDS) cases declined for the first time since the epidemic began. The decrease occurred predominantly in white males, whereas in blacks with heterosexual exposures for risk factors, the incidence actually increased. Also in 1995, the number of AIDS-related deaths declined for the first time. If these trends continue, we can expect a continued increase in the number of blacks living with AIDS. We estimate that 1% to 4% will develop renal failure from HIVAN. The incidence of HIVAN can be expected to increase unless new approaches are successful in preventing the spread of HIV-1 in all segments of the population or in treating the renal complications of HIV-1 infection. PMID: 9692350

J Acquir Immune Defic Syndr. 2006 May;42(1):1-11.

HIV-1 infection initiates an inflammatory cascade in human renal tubular epithelial cells.

Ross MJ, Fan C, Ross MD, Chu TH, Shi Y, Kaufman L, Zhang W, Klotman ME, Klotman PE. Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA. michael.ross@mssm.edu
HIV-associated nephropathy (HIVAN) is the most common cause of chronic renal failure in HIV-infected patients. Tubulointerstitial inflammation is a prominent component of the histopathology of HIVAN. The pathogenesis of HIVAN is a result of infection of renal epithelial cells, but the cellular response to this infection remains poorly defined. In these studies, we used oligonucleotide microarrays to identify differentially expressed genes in renal tubular epithelial cells from a patient with HIVAN at three time points after infection with vesicular stomatitis virus-pseudotyped gag/pol-deleted HIV-1. Very few genes were differentially expressed 12 and 24 hours after infection. Three days after infection, however, 47 genes were upregulated by at least 1.8-fold. The most prominent response of these cells to HIV-1 expression was production of proinflammatory mediators, including chemokines, cytokines, and adhesion molecules. Many of the upregulated genes are targets of interleukin 6 and nuclear factor kappa B regulation, suggesting a central role for these proteins in the response of tubular epithelial cells to HIV-1 infection. Analysis of kidneys from HIV-1 transgenic mice revealed upregulation of many of the proinflammatory genes identified in the microarray studies. These studies provide novel insights into the mechanisms by which HIV-1 infection of tubular epithelial cells leads to tubulointerstitial inflammation and progressive renal injury. PMID: 16763488

HTLV-1 also implicated

Adult T cell leukemia in hemodialysis patients from the Kagoshima district, an area in which human T cell leukemia virus type I is highly endemic.

We report 2 cases of adult T cell leukemia (ATL) from hemodialysis (HD) patients with chronic renal failure (CRF) in the Kagoshima district, an endemic area of human T cell leukemia virus type I(HTLV-I) in Japan. The positivity of antibodies to ATL-associated antigen(anti-ATLA) in HD patients, regardless of whether or not blood transfusions were given, has been higher than in healthy persons in the district (p less than 0.01). ATL is considered to break out from HTLV-I carriers. Further study should be conducted to clarify the relationship between HTLV-I infection and CRF, and moreover, attention should be directed not only to treatment of HD but accompanying ATL as well, particularly in HTLV-I-endemic areas. Uematsu T, Hanada S, Saito T, Otsuka M, Komidori K, Osaki K, Uemura S, Ueda H, Harada R, Hashimoto S. Second Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Japan. Nephron. 1989;51(2):257-60.
PMID: 2915764

as well as feline retrovirus

J Am Vet Med Assoc. 2010 Feb 15;236(4):424-9.

Association between naturally occurring chronic kidney disease and feline immunodeficiency virus infection status in cats.

White JD, Malik R, Norris JM, Malikides N. Faculty of Veterinary Science, University of Sydney, NSW, Australia. J.White@massey.ac.nz
OBJECTIVE: To investigate the association between naturally occurring chronic kidney disease (CKD) and FIV infection status in cats in Australia. DESIGN: Case-control study. ANIMALS: 73 cats with CKD and 69 cats without historical, physical, or clinicopathologic evidence of CKD. PROCEDURES: Cats were tested for serum antibodies against FIV glycoprotein 40 (gp40) by use of an immunomigration assay. Information regarding age, breed (purebred or domestic), and sex was obtained from medical records. Analysis was performed on data from cats stratified into 2 age categories (< 11 years old and >or= 11 years old). Univariable and then multivariable analyses were performed to investigate the relationship between CKD and the study variable (FIV infection), the latter analysis accounting for breed (purebred or domestic), sex, and veterinary hospital of origin. RESULTS: Results of multivariable analysis revealed that younger cats with CKD (< 11 years old) were significantly more likely to have positive test results for serum antibodies against FIV gp40 than were cats without CKD. No significant associations were found between CKD and FIV infection, breed, sex, or hospital of origin among older (>or= 11 years old) cats in the multivariable analysis. CONCLUSIONS AND CLINICAL RELEVANCE: Among cats < 11 years of age, those with CKD were significantly more likely to have positive test results for serum antibodies against FIV gp40 than were cats without CKD. It cannot be definitively established from results of this study whether infection with FIV preceded the development of CKD, and the role, if any, of FIV in the establishment or progression of CKD remains to be determined.
PMID: 20151865


Senior Member
Renal transplantation in patients with HIV

Thank you very much for posting this research Natasa

BTW I find it interesting that researchers are using MMF to treat children with Juvenile Batten Disease, a fatal neurodegenerative disease in children

Quote " However, many agents currently used for post-transplantation maintenance immunosuppression (for example, MMF, ciclosporin, tacrolimus, and sirolimus) have antiretroviral properties."

Strategies for immunosuppression

As mentioned, the reasonable belief that immunosuppression could result in progression of HIV disease has in the past discouraged transplantation in people with HIV. However, many agents currently used for post-transplantation maintenance immunosuppression (for example, MMF, ciclosporin, tacrolimus, and sirolimus) have antiretroviral properties. MMF virostatic action is thought to result from the depletion it causes of guanoside nucleosides, which are necessary for the virus lifecycle.44, 45 Ciclosporin and tacrolimus have well-documented antiretroviral effects through selective inhibition of infected cell growth.46, 47 These two agents interfere with HIV pathogenic protein functions, which ultimately results in the reduction of virus formation.48 Ciclosporin and tacrolimus can, however, cause glucose intolerance, which can be exacerbated by administration of sirolimus.

Since many patients with renal allografts, particularly those with HIV, experience some degree of renal insufficiency, sirolimus, an inhibitor of the mammalian target of rapamycin and an antiproliferative agent, has been considered as an alternative to CNIs. Similarly to CNIs, sirolimus also exerts some antiretroviral activity through suppression of T-cell activation, suppression of professional antigen presenting cell function, and disruption of infective virion replication.35, 36 Sirolimus also decreases the expression of C–C chemokine receptor type 5 on monocytes and lymphocytes, thus potentially preventing the HIV virus from entering these cells and replicating.37

In the initial clinical trials of organ transplantation in patients with HIV,20, 21 immunosuppressive regimens focused on maintenance therapy with agents with known antiretroviral qualities. This therapy consisted of a combination of steroids, a CNI and MMF. However, organ recipients with HIV can mount an alloimmune response20, 21 and renal transplant recipients with HIV have a higher rejection rate than their counterparts without HIV.20, 21 For this reason, induction therapy with interleukin 2 receptor inhibitor has been introduced.26, 27 Whether induction with even more potent immunosuppressants than interleukin 2 receptor inhibitor will be required is unknown. Nonetheless, most transplantation centers are reluctant to use lymphocyte-depleting agents for induction, as these agents severely deplete CD4+ T cells for several months. Nonetheless, these agents have successfully reversed aggressive rejection in several patients.21



Senior Member
Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase,

J Acquir Immune Defic Syndr. 1999 Aug 15;21(5):362-70.

Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity.
Margolis D, Heredia A, Gaywee J, Oldach D, Drusano G, Redfield R.

The use of inhibitors of purine nucleoside metabolism has been advocated for the treatment of HIV-1 infection. Abacavir is the first clinically available guanosine analogue HIV-1 reverse transcriptase inhibitor, and the most potent nucleoside analogue yet developed. Mycophenolic acid (MA), a specific inhibitor of lymphocyte proliferation that is currently in use in organ transplantation, acts on inosine monophosphate dehydrogenase to block conversion of inosine monophosphate to guanosine monophosphate. We found abacavir and MA inhibited HIV-1 replication in stimulated peripheral blood mononuclear cells (PBMCs) and in monocyte-derived macrophages (MDMs). Inhibition was potent and synergistic to an extent not previously observed with other antiretroviral combinations. MA was effective at concentrations (0.25 microM) far below those used for immunosuppression in organ transplantation. An HIV strain encoding the M184V mutation was susceptible to the combination of MA and abacavir. However, the combination of MA and zidovudine (ZDV) or stavudine (d4T) was antagonistic. Although the translation of these observations must be carefully evaluated in clinical trials, the judicious combination of antiretrovirals and inhibitors of nucleoside metabolism may emerge as an important strategy in the treatment of HIV infection.



Senior Member
HIV-1 entry into human podocytes is mediated through lipid rafts

HIV-1 entry into human podocytes is mediated through lipid rafts
Joanna Mikulak1 and Pravin C Singhal1

To the Editor: We read with the interest the article by Khan et al.1 Lipid rafts have been reported to have an important role for human immunodeficiency virus (HIV)-1 entry into several cells.2, 3 Renal biopsy studies have demonstrated that HIV-1 infection of renal epithelial cells contribute to the pathogenesis of HIV-1-associated nephropathy.4, 5 As renal epithelial cells do not express classical HIV-1 receptors, their entry into podocytes remains a mystery.6 We studied the role of lipid rafts in the entry of HIV-1 into podocytes. Conditionally immortalized human podocytes were exposed to primary strains of HIV-1 with different co-receptor usageR5 HIV-192US660 and X4 HIV-192HT599. As shown in Figure 1a, human podocytes exposed to either R5 or X4 viral strains were positive for HIV-1-specific strong-stop DNA (LTR RU5).

To determine the role of lipid rafts, we evaluated the effect of methyl-β-cyclodextrin (MβCD) on podocyte HIV-1 entry. MβCD is a derivative of cyclic oligosaccharides and has a lipophilic property that extracts cholesterol from membranes, resulting in lipid rafts disruption.7 To test the drug effect of MβCD on mock-infected podocytes, we used the cholera toxin B-subunit, a specific marker for the lipid rafts associated GSL GM1.8 MβCD treatment decreased approximately 70% podocyte cholesterol expression (Figure 1b). As shown in Figure 1c, podocyte viral accumulation significantly decreased after MβCD treatment when compared with the mock-treated control. As cholesterol-replenished cells (first exposed to cyclodextrin and then replenished with exogenous water-soluble cholesterol) showed comparable levels of viral entry (as observed in untreated cells), it appeared that the inhibition of HIV-1 entry was not due to the potential toxicity of MβCD (Figure 1d). Inhibition of viral entry after cholesterol extraction was independent of viral tropism (data not shown). These results support the notion that cholesterol (maintenance of lipid raft integrity) is required for entry of both X4 and R5 HIV-1. continued...