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Biomedical subjects

R Draenert

Publications and source records attributed to R Draenert.

13 recordsLinked to original sources
PubMed2006

HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy.

Renal disease is becoming an increasingly prevalent entity in human immunodeficiency virus (HIV)-infected patients; it occurs in a variety of clinical settings and is associated with histopathological changes. HIV-related renal impairment can present as acute or chronic kidney disease; it can be caused directly or indirectly by HIV and/or by drug-related effects that are directly nephrotoxic or lead to changes in renal function by inducing metabolic vaculopathy and renal damage. Acute renal failure is frequently caused by the toxic effects of antiretroviral therapy or nephrotoxic antimicrobial substances used in the treatment of opportunistic infections. Chronic renal disease can be caused by multiple pathophysiological mechanisms, leading to HIV-associated nephropathy, a form of collapsing focal glomerulosclerosis, thrombotic microangiopathy, and various forms of immune complex glomerulonephritis. The increase in life expectancy and alteration of lipid metabolism due to receipt of highly active antiretroviral therapy are expected to result in an increased prevalence of diabetes and hypertension and, thus, to secondary diabetic and hypertensive renal damage. Antiretroviral agents, such as indinavir and tenofovir, have been associated with nephrotoxic drug effects that have been shown to be reversible in most cases. In this article, we review the current knowledge about acute and chronic HIV-associated renal disease, metabolic alterations and related nephropathies, and toxic drug effects of combination antiretroviral pharmacotherapy.

AIDS-Associated Nephropathy↗
PubMed2005

[Options in HIV therapy: present and future].

Highly active antiretroviral therapy (HAART) has markedly decreased HIV-associated mortality. It consists of a combination of three antiretroviral drugs from four different classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and inhibitors of virus-cell fusion. Increasing resistance against antiretroviral drugs calls for the development of new compounds and drug classes. The growing understanding of molecular mechanisms in HIV-replication led to the identification of further steps which might serve as novel antiretroviral targets. Uninfected cells could be protected from HIV by inhibiting extracellular binding mechanisms. Improvement of existing antiretroviral drugs and further development of novel therapeutic targets will enrich antiretroviral treatment.

Anti-Retroviral Agents↗
PubMed2004

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Adult↗
PubMed2004

What's new in HIV/AIDS. Protective immunity in HIV infection: where do we stand?

In the face of a global epidemic of HIV/AIDS with the majority of individuals living in the developing countries, a protective vaccine seem the foremost goal. As this is not within imminent reach, the other option would be immunotherapy that prolongs the asymptomatic phase of infection. The basis for such a therapy is to understand the correlates of protective immunity against HIV. Here we present the most recent advances regarding selected parts of the immune response towards HIV.

AIDS Vaccines↗
PubMed2004

Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection.

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/ micro l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

Amino Acid Sequence↗
PubMed2004

Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities.

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

AIDS Vaccines↗
PubMed2003

[Adverse effects of antiretroviral therapy. Aspects of pathogenesis].

Highly active antiretroviral therapy has resulted in remarkable reduction of morbidity and mortality of HIV infection. With increasing duration of therapy metabolic alterations such as hyperlipidemia, diabetes mellitus type 2 and lipodystrophy are encountered which considerably reduced quality of life for the patients. These adverse events are most likely due to protease inhibitors and nucleoside analogues with synergistic effects. The pathogenesis is related to metabolic alterations of the adipocytes with cellular insulin resistance and enhanced apoptosis of these cells caused by adipocytic cytokines such as adiponectin, leptin, TNF-alpha and interleukin 2. Switch of therapy regimens with elimination of the most suspicious substances and certain protease inhibitors can lead to improvement of deranged metabolism. Also symptomatic therapy is possible to cope with hyperlipidemia and diabetes, although no effective treatment is available to reverse already existing lipodystrophy. Our knowledge about the pathogenesis of these alterations might lead to new concepts and causal therapy in the future.

Anti-HIV Agents↗
PubMed2003

Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load.

Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/10(6) PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Effects of sodium selenite on deoxycholic acid-induced hyperproliferation of human colonic mucosa in short-term culture.

It has been shown that in vitro incubation of human colonic biopsies with the secondary bile acid deoxycholic acid (DCA) leads to the hyperproliferation of colonic crypt cells with an expansion of the proliferative zone, which is regarded as a biomarker of increased cancer risk. Sodium selenite (SSE), on the other hand, has been implicated as a protective agent in experimental studies, but toxic effects were reported as well, depending on the dose of SSE. To elucidate the effects of SSE on human colonic mucosa, biopsies from endoscopically normal sigmoid colon tissue of 30 subjects were incubated with 5 microM DCA or a combination of 5 microM DCA and SSE in concentrations of 5, 10, 20, 50, 80, and 100 microM, respectively. Equimolar NaCl incubations served as a control. Proliferating cells were labeled by bromodeoxyuridine immunohistochemistry, and the labeling index (LI) was computed. In the experiments using 5, 10, and 20 microM SSE, the whole crypt LI was significantly lower after DCA + SSE incubation (0.136, 0.118, and 0.110, respectively) compared to that after incubation with DCA alone (0.172, 0.157, and 0.165, respectively; P < 0.01). The corresponding LIs during DCA + SSE incubation were comparable to the LIs obtained after NaCl incubation (average LI = 0.14). Contrary to this finding, severe cell damage was observed in the biopsies that were incubated with the higher SSE concentrations of 50 microM and above. The antiproliferative effects of SSE may indicate a possible protective effect in the prevention of human colon cancer development. However, the observed toxic effects of higher SSE concentrations strongly suggest the need for additional studies before general recommendations for the use of SSE in colon cancer prevention can be made.

Adult↗