Opportunistic Infection Complicating Acquired Immune Deficiency Syndrome

Lerner, Chester W.; Tapper, Michael L.

doi:10.1097/00005792-198405000-00002

Cited by 104 publications

(29 citation statements)

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“…About 50% of young women have already developed antibodies against cyto megalovirus (CMV) [1], In case of immunosuppression by lymphoma, generalized malignancies, in patients with transplantations, in HIV-positive patients as well as in pregnancy, a primary CMV infection, a reactivation of a latent virus or a reinfection by an exogenetic virus is frequently reported. Especially in patients with acquired immunodeficiency syndrome (AIDS) cytomegaly-related pneumonia, encephalitis, bleeding esophagus ulceration, ulceration of stomach and intestines, hepatitis, cholecys titis and retinitis are known [2].…”

Section: Introductionmentioning

confidence: 99%

Disseminated Cytomegalovirus Infection of the Female Genital Tract (With 1 color plate)

Friedmann¹,

Schäfer²,

Kretschmer

et al. 1991

Gynecol Obstet Invest

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Section: Introductionmentioning

confidence: 99%

Disseminated Cytomegalovirus Infection of the Female Genital Tract (With 1 color plate)

Friedmann¹,

Schäfer²,

Kretschmer

et al. 1991

Gynecol Obstet Invest

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“…Although a substantial portion of the global adult population is currently HCMV-seropositive, a functional immune system can hold the virus in check. For immunocompromised individuals, on the other hand, infection with HCMV presents a severe threat (1)(2)(3). Accordingly, antiviral therapy is used as both prophylaxis and therapeutic strategies in solid organ transplant recipients, who receive concomitant immunosuppressants.…”

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confidence: 99%

Phosphonoformic Acid Inhibits Viral Replication by Trapping the Closed Form of the DNA Polymerase

Zahn

Tchesnokov

Götte

et al. 2011

Journal of Biological Chemistry

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Phosphonoformic acid (PFA, foscarnet) belongs to a class of antiviral drugs that inhibit the human cytomegalovirus DNA polymerase (UL54) by mimicking the pyrophosphate leaving group of the nucleotide transfer reaction. Difficulties expressing UL54 have hampered investigation of the precise structural requirements rendering inhibition by this drug. However, a previously engineered chimeric DNA polymerase, constructed by mutating the homologous polymerase from bacteriophage RB69 (gp43) to express several variable elements from UL54, can bypass this obstacle because of its favorable expression and acquired sensitivity to PFA (Tchesnokov, E. P., Obikhod, A., Schinazi, R. F., and Götte, M. (2008) J. Biol. Chem. 283, 34218 -34228). Here, we compare two crystal structures that depict the chimeric DNA polymerase with and without PFA bound. PFA is visualized for the first time in the active site of a DNA polymerase, where interactions are resolved between the PP i mimic and two basic residues absolutely conserved in the fingers domain of family B polymerases. PFA also chelates metal ion B, the cation that contacts the triphosphate tail of the incoming nucleotide. These DNA complexes utilize a primer-template pair enzymatically chain-terminated by incorporation of acyclo-GMP, the phosphorylated form of the anti-herpes drug acyclovir. We postulate that the V478W mutation present in the chimera is critical in that it pushes the fingers domain to more readily adopt the closed conformation whether or not the drug is bound. The closed state of the fingers domain traps the variant polymerase in the untranslocated state and increases affinity for PFA. This finding provides a model for the mechanism of UL54 stalling by PFA. The human cytomegalovirus (HCMV)3 belongs to the herpesviridae family, into which several important human pathogens are classified. A primary infection of this virus in pregnant mothers can be devastating to the developing fetus, resulting in several congenital disorders. Although a substantial portion of the global adult population is currently HCMV-seropositive, a functional immune system can hold the virus in check. For immunocompromised individuals, on the other hand, infection with HCMV presents a severe threat (1-3). Accordingly, antiviral therapy is used as both prophylaxis and therapeutic strategies in solid organ transplant recipients, who receive concomitant immunosuppressants. In this setting, infection with the virus is a major cause of morbidity and mortality.The limited pharmacological options available for treatment of HCMV largely consist of nucleoside analog inhibitors that target the gene product of UL54, a family B DNA polymerase. Although some inhibitors, such as cidofovir, are chemically synthesized as acyclic nucleoside phosphonates, most nucleoside analogs require monophosphorylation by a viral kinase, such as UL97 in HCMV, before other cellular kinases convert these drugs into triphosphorylated substrates of the DNA polymerase (4). Following incorporation into the viral DNA, these non-n...

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“…The spectrum of disease caused by Candida ranges from superficial infections of the skin and mucosa to severe systemic disease in individuals with impaired immunity (5,6). Recently, Candida has emerged as a common source of hospital-acquired infections.…”

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confidence: 99%

A Candida albicans dispersed, repeated gene family and its epidemiologic applications.

Scherer

Stevens

1988

Proc. Natl. Acad. Sci. U.S.A.

254

199

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Candida albicans causes a wide variety of infections but can readily be isolated from the skin and mucosa of healthy individuals. To enable high-resolution epidemiologic studies on this common pathogen, a species-specific DNA probe has been isolated from its genome. There are w10 copies of the sequence dispersed among the chromosome-sized DNA molecules resolved by pulsed-field electrophoresis. New DNA polymorphisms in this gene family arise at high rates. As a consequence, this probe will readily distinguish strains from different patients in the same hospital and from various sites in individual patients. The DNA polymorphisms detected by using this probe are largely due to internal changes in members of the family rather than movement to new genomic locations. This suggests recombination or gene conversion rather than transposition as the mechanism producing the observed variation.

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Opportunistic Infection Complicating Acquired Immune Deficiency Syndrome

Cited by 104 publications

References 0 publications

Disseminated Cytomegalovirus Infection of the Female Genital Tract (With 1 color plate)

Disseminated Cytomegalovirus Infection of the Female Genital Tract (With 1 color plate)

Phosphonoformic Acid Inhibits Viral Replication by Trapping the Closed Form of the DNA Polymerase

A Candida albicans dispersed, repeated gene family and its epidemiologic applications.

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