Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reverse transcriptase of the human immunodeficiency virus type 1 (HIV-1 RT) does not possess an exonucleolytic proofreading activity; however, previous studies have shown that this enzyme can excise incorporated chain-terminators in the presence of pyrophosphate or ATP. This type of reaction provides a plausible mechanism for HIV-1 resistance to several nucleoside analogue inhibitors. Here we studied the efficiency of pyrophosphorolysis in the context of mismatched nucleotides, and found that the removal of dCMP and dTMP opposite T is literally blocked. Thus, pyrophosphorolysis may not provide an alternative, universal proofreading mechanism, although excision of dGMP and the correct dAMP opposite T can occur with considerable efficiency. Site-specific footprinting experiments revealed that the 3' end of C:T- and T:T-mispaired primer strands is predominantly found in a post-translocational configuration, which prevents the removal of terminal nucleotides. In contrast, complexes containing G:T and A:T base pairs can exist in both post- and pre-translocational stages. Excision can only occur in the latter, which helps to explain the observed selectivity of the reaction. The efficiency of mismatch extensions does not appear to depend on pre-existing changes of the translocational equilibrium. However, footprints of complexes containing 3' penultimate mismatches suggest that the incorporation of the first nucleotide following the mispair can force the enzyme to slide backwards, which can inhibit ensuing polymerization events. The fact that misincorporated nucleotides can affect the precise positioning of RT provides a rational for the development of novel nucleoside analogue inhibitors that contain modifications in the base moiety.
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PMID:Impact of the translocational equilibrium of HIV-1 reverse transcriptase on the efficiency of mismatch extensions and the excision of mispaired nucleotides. 1518 47

HIV-1 reverse transcriptase can remove chain terminators from blocked DNA ends through a nucleotide-dependent mechanism. We show that the catalytic efficiency of the removal reaction can vary several hundred-fold in different sequence contexts and is most strongly affected by the nature of the base pair at the 3'-primer terminus and the six base pairs upstream of it. Similar effects of the upstream sequence were observed with primer-templates terminated with 2',3'-dideoxy-AMP, 2',3'-dideoxy-CMP, or 2',3'-dideoxy-GMP. However, the removal of 2',3'-dideoxy-TMP or 3'-azido-2',3'-dideoxy-TMP was much less influenced by upstream primer-template sequence, and the rate of excision of these thymidylate analogues was greater than or equal to that of the other chain-terminating residues in each sequence context tested. These results strongly indicate that the primer terminus and adjacent upstream base pairs interact with reverse transcriptase in a sequence-dependent manner that affects the removal reaction. We conclude that primer-template sequence context is a major factor to consider when evaluating the removal of different chain terminators by HIV-1 reverse transcriptase.
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PMID:Effects of primer-template sequence on ATP-dependent removal of chain-terminating nucleotide analogues by HIV-1 reverse transcriptase. 1530 46

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.
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PMID:Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. 1550 56

Oligoribonucleotides containing 8-oxo-7,8-dihydroguanosine (8-oxoG) and 8-oxo-7,8-dihydro-2'-O-methylguanosine (8-oxoG-Me) were synthesized. The base pairing properties of 8-oxoG and 8-oxoG-Me in oligoribonucleotide in cDNA synthesis by reverse transcriptases were studied. dCMP was preferentially incorporated into the site opposite 8-oxoG or 8-oxoG-Me than into other dNMPs. TMP and dCMP were inserted preferentially into sites opposite 8-oxoG or 8-oxoG by reverse transcriptases. HIV-RT did not incorporate TMP, but RAV2-RT incorporated 50% more TMP than dCMP into the site opposite 8-oxoG. In the site opposite 8-oxoG-Me TMP was substantially incorporated by HIV-RT or RAV2-RT. Thermodynamic analysis of the DNA.RNA heteroduplex containing 8-oxoG revealed that 8-oxoG and 8-oxoG-Me formed base pairs with cytidine and thymidine with similar stability. The thermodynamic parameter (DeltaG degrees ) demonstrated that the formation of duplexes between 8-oxoG or 8-oxoG-Me and cytidine or thymidine is more thermodynamically favorable than with adenosine and guanosine. However, differences in the melting temperature and DeltaG degrees 's of 8-oxoG/dC and 8-oxoG/T were much smaller than between G/dC and G/T. CD spectra showed that DNA . RNA containing 8-oxoG or 8-oxoG-Me duplexes showed similarities between the A-type RNA and B-type DNA conformations.
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PMID:DNA . RNA heteroduplex containing 8-oxo-7,8-dihydroguanosine: base pairing, structures, and thermodynamic stability. 1560 23

Pyrophosphate analogues, namely, pyrophosphorous, hypophosphoric, and hypophosphorous acids, were evaluated as inhibitors in elongation reactions and substrates in pyrophosphorolysis reaction catalyzed by HIV-1 reverse transcriptase and DNA polymerase I (the Klenow fragment). The substrate efficacy of hypophosphoric acid in pyrophosphorolysis reaction exceeded that of pyrophosphate for both enzymes by more than ten times. The product of the reaction was a dNTP analogue bearing a hypophosphate in the beta,gamma-position. Pyrophosphorous and hypophosphorous acids were neither inhibitors nor substrates for the enzymes. Kinetic parameters of the pyrophosphorolysis reaction catalyzed by HIV reverse transcriptase in the presence of hypophosphoric acid were evaluated. The dTMP analogue bearing a hypophosphate in the beta,gamma-position was synthesized and its substrate properties in elongation reaction catalyzed by HIV-1 reverse transcriptase were similar to those of natural dTTP. Hypophosphoric acid was capable of removing ddTMP, ddTMP(3'N3), and ddTMP(3'NH2) from the 3'-end of primers with an equal efficacy.
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PMID:Hypophosphoric acid is a unique substrate of pyrophosphorolysis catalyzed by HIV-1 reverse transcriptase. 1627 6

We report a case of dual Mycobacterium tuberculosis (TB) and Pneumocystis jiroveci (carinii) (PCP) lymphadenitis in a patient with HIV who had been receiving trimethoprim-sulfamethoxazole (TMP-SMX) as systemic prophylaxis for PCP. This patient was successfully treated with antituberculosis medications and TMP-SMX. Our review of the literature identified this as the first reported case of dual TB and PCP lymphadenitis in an HIV-infected host and highlights the potential limitations of TMP-SMX prophylaxis.
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PMID:Dual infection with Mycobacterium tuberculosis and Pneumocystis jiroveci Lymphadenitis in a Patient with HIV infection: case report and review of the literature. 1642 50

Daily prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) significantly decreases morbidity and mortality among people living with HIV. Some clinicians are reluctant to use TMP-SMZ in pregnant and breastfeeding HIV-infected women because of concerns about the possible teratogenicity when used in the first trimester and about its potential to induce hyperbilirubinemia near term and during early breastfeeding. We systematically reviewed evidence regarding the toxicity of TMP-SMZ prophylaxis in pregnant and breastfeeding women to help guide practice in resource-limited settings. We identified relevant literature by searching PubMed and MEDLINE via OVID, Embase, and Science Citation Index for data on hyperbilirubinemia, kernicterus, and teratogenicity associated with administration of sulfonamides and TMP-SMZ through July 2005. We also reviewed the reference lists of identified articles. Most studies demonstrated that TMP-SMZ was not associated with hyperbilirubinemia when administered to mothers during pregnancy and breastfeeding. No cases of kernicterus were reported in neonates after maternal ingestion of sulfonamides. There is mixed evidence linking ingestion of TMP-SMZ and other sulfonamides in early pregnancy to elevated risks of oral clefts, neural tube defects, and cardiovascular and urinary tract abnormalities, although some sources found that supplementation with folic acid might ameliorate this potential risk. Existing guidelines recommend that HIV-infected pregnant women receive prophylaxis, but they differ with regards to stage of disease at which to initiate treatment, need for CD4+ T-lymphocyte testing, and prophylaxis during the first trimester. Existing data indicate that the risk of serious injury to neonates from maternal use of daily TMP-SMZ prophylaxis during pregnancy and breastfeeding is small. Given the substantial benefits of TMP-SMZ prophylaxis for HIV-infected women living in resource-limited settings, this review indicates that it is safe to abide by the WHO guidelines recommending daily TMP-SMZ prophylaxis for HIV-infected pregnant women.
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PMID:Systematic review of the safety of trimethoprim-sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings. 1673 49

Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTI) have become increasingly common. This study's objectives were to describe the clinical spectrum of MRSA in a community health center and to determine whether the use of specific antimicrobials correlated with increased probability of clinical resolution of SSTI. A retrospective chart review of 399 sequential cases of culture-confirmed S. aureus SSTI, including 227 cases of MRSA SSTI, among outpatients at Fenway Community Health (Boston, MA) from 1998 to 2005 was done. The proportion of S. aureus SSTI due to MRSA increased significantly from 1998 to 2005 (P<0.0001). Resistance to clindamycin was common (48.2% of isolates). At the beginning of the study period, most patients with MRSA SSTI empirically treated with antibiotics received a beta-lactam, whereas by 2005, 76% received trimethoprim-sulfamethoxazole (TMP-SMX) (P<0.0001). Initially, few MRSA isolates were sensitive to the empirical antibiotic, but 77% were susceptible by 2005 (P<0.0001). A significantly higher percentage of patients with MRSA isolates had clinical resolution on the empirical antibiotic by 2005 (P=0.037). Use of an empirical antibiotic to which the clinical isolate was sensitive was associated with increased odds of clinical resolution on empirical therapy (odds ratio=5.91), controlling for incision and drainage and HIV status. MRSA now accounts for the majority of SSTI due to S. aureus at Fenway, and improved rates of clinical resolution on empirical antibiotic therapy have paralleled increasing use of empirical TMP-SMX for these infections. TMP-SMX appears to be an appropriate empirical antibiotic for suspected MRSA SSTI, especially where clindamycin resistance is common.
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PMID:Treatment and outcomes of infections by methicillin-resistant Staphylococcus aureus at an ambulatory clinic. 1711 64

HIV-1 can become resistant to nucleoside analogs by developing an enhanced ability to excise the analogs after they have been incorporated. Excision requires that the analog be located at the 3' terminus of the primer. We have describe nucleoside analogs that do not block DNA synthesis at the point of incorporation, but only after additional dNTPs have been added to the DNA. These nucleoside analogs are called "delayed chain terminators" and are relatively effective inhibitors of drug-resistant HIV-1 reverse transcriptases (RTs) that are excision proficient. However, the first delayed chain terminator that we characterized was poorly phosphorylated in cultured cells. We have examined other nucleoside analogs to determine whether these compounds also act as delayed chain terminators, but were more efficiently converted to the triphosphate form by cellular kinases. These analogs contain substitutions on the deoxyribose sugar ring at the 4' carbon (4'C-methyl dT and 4'C-ethyl dT). Unlike true delayed chain terminators, which terminate DNA synthesis in a spatial sense (DNA synthesis is halted only after additional dNTPs have been incorporated after the analog), 4'C-methyl dTTP causes a pause in DNA synthesis at the point of incorporation. However, HIV-1 RT can eventually extend the primer blocked by the 4' C-Me dTMP analog. 4'C-methyl dTTP blocks DNA synthesis in a temporal sense, rather than in a spatial sense. A primer blocked by 4'C-ethyl dTMP is not extended by HIV-1 RT, and this compound acts like a conventional chain terminator, despite the presence of a 3'-OH group. These compounds effectively block the replication of an HIV-1-based vector that replicates using wild-type HIV-1 RT, but only in the presence of herpes simplex virus thymidine kinase (HSV TK). These compounds are effective against many NRTI drug-resistant RT variants; however, the M184V mutant is relatively resistant.
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PMID:The nucleoside analogs 4'C-methyl thymidine and 4'C-ethyl thymidine block DNA synthesis by wild-type HIV-1 RT and excision proficient NRTI resistant RT variants. 1759 54

A 76-year-old man, who was in the hospital for the treatment of type 2 diabetes mellitus and was receiving gonadotropin-releasing hormone (GnRH) agonist treatment for prostate cancer, developed fever and hypoxemia. Imaging revealed diffuse interstitial shadows, and PCR of the bronchoalveolar lavage fluid was positive for Pneumocystis jirovecii. The patient's absolute CD4-positive lymphocyte count dropped to 145/microl, but the HIV antibody was negative. After trimethoprim-sulfamethoxazole (TMP/SXT) treatment, the absolute CD4 positive lymphocyte count returned to normal. This patient with type 2 diabetes mellitus developed Pneumocystis pneumonia and developed a transient decrease in CD4-positive lymphocytes.
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PMID:Pneumocystis pneumonia in a patient with type 2 diabetes mellitus. 1763 14


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