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)

It was reported at the 1995 Second National Retrovirus Conference that AIDS has now surpassed unintentional injury as the leading cause of death for male Americans between the ages of 25 to 44, and for women, AIDS is fourth behind unintentional injury. A study of multidrug resistant tuberculosis that showed improved survival rates as long as appropriate therapy began within four weeks of diagnosis was also presented. The current recommendation is to consider the PPD skin test positive in persons with HIV if the bump that appears is over five millimeters in diameter. A new ganciclovir implant study demonstrated the implant's effectiveness in preventing CMV disease progression with low rates of complications, suggesting implants should probably replace intravenous ganciclovir as maintenance therapy. Another study demonstrated the effectiveness of cidofovir as a treatment for CMV infection, indicating that cidofovir was appropriate as a salvage therapy for those failing ganciclovir and foscarnet. In vitro studies involving Taxol and Kaposi's sarcoma (KS) show partial responses (55 percent), and some disease stabilization (40 percent). Four of five patients with pulmonary KS responded with clearance of tumor lesions. The first randomized trial involving Loviride with zidovudine has shown a sustained increase in CD4 cells with headache, nausea, and diarrhea as the most common side effects. Preliminary assessments reveal a reduction in viral load using the combination as opposed to monotherapy. Additional Loviride combination trials are being planned in Europe.
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PMID:Second National Retrovirus conference: a further report. 1136 59

Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are widely used in the treatment of HIV infection. Loviride (an alpha-APA derivative) and HBY 097 (a quinoxaline derivative) are two potent non-nucleoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of drug-resistant mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic pocket that binds NNRTIs. Substitution of asparagine for lysine at position 103 of HIV-1 RT is associated with the development of resistance to NNRTIs; this mutation contributes to clinical failure of treatments employing NNRTIs. We have determined the structures of the unliganded form of the Lys103Asn mutant HIV-1 RT and in complexes with loviride and HBY 097. The structures of wild-type and Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type and Lys103Asn mutant HIV-1 RT structures reveals a network of hydrogen bonds in the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water molecules in the pocket and nearby pocket residues. The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could interfere with the ability of inhibitors to bind to the enzyme. These results are consistent with kinetic data indicating that NNRTIs bind more slowly to Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to different classes of NNRTIs. Design of NNRTIs that make favorable interactions with the Asn103 side-chain should be relatively effective against the Lys103Asn drug-resistant mutant.
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PMID:The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. 1137 Nov 63