The development of an effective human immunodeficiency virus type 1 (HIV-1) vaccine is likely to depend on knowledge of circulating variants of genes other than the commonly sequenced gag andenv genes. In addition, full-genome data are particularly limited for HIV-1 subtype C, currently the most commonly transmitted subtype in India and worldwide. Likewise, little is known about sequence variation of HIV-1 in India, the country facing the largest burden of HIV worldwide. Therefore, the objective of this study was to clone and characterize the complete genome of HIV-1 from seroconverters infected with subtype C variants in India. Cocultured HIV-1 isolates were obtained from six seroincident individuals from Pune, India, and virtually full-length HIV-1 genomes were amplified, cloned, and sequenced from each. Sequence analysis revealed that five of the six genomes were of subtype C, while one was a mosaic of subtypes A and C, with multiple breakpoints in env,nef, and the 3′ long terminal repeat as determined by both maximal χ2 analysis and phylogenetic bootstrapping. Sequences were compared for preservation of known cytotoxic T lymphocyte (CTL) epitopes. Compared with those of the HIV-1LAI sequence, 38% of well-defined CTL epitopes were identical. The proportion of nonconservative substitutions for Env, at 61%, was higher (P < 0.001) than those for Gag (24%), Pol (18%), and Nef (32%). Therefore, characterized CTL epitopes demonstrated substantial differences from subtype B laboratory strains, which were most pronounced in Env. Because these clones were obtained from Indian seroconverters, they are likely to facilitate vaccine-related efforts in India by providing potential antigens for vaccine candidates as well as for assays of vaccine responsiveness.

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

Hepatitis C virus (HCV) infection is a major health problem in Egypt, where the seroprevalence is 10-20-fold higher than that in the United States. To characterize the HCV genotype distribution and concordance of genotype assessments on the basis of multiple genomic regions, specimens were obtained from blood donors in 15 geographically diverse governorates throughout Egypt. The 5' noncoding, core/E1, and NS5B regions were amplified by reverse transcription-polymerase chain reaction and analyzed by both restriction fragment length polymorphism (RFLP) and phylogenetic tree construction. For the 5' noncoding region, 122 (64%) of 190 specimens were amplified and analyzed by RFLP: 111 (91%) were genotype 4, 1 (1%) was genotype 1a, 1 (1%) was genotype 1b, and 9 (7%) could not be typed. Phylogenetic analyses of the core/E1 and NS5B regions confirmed the genotype 4 preponderance and revealed evidence of 3 new subtypes. Analysis of genetic distance between isolates was consistent with the introduction of multiple virus strains 75-140 years ago, and no clustering was detected within geographic regions, suggesting widespread dispersion at some time since then.