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The TALLYHO/JngJ (TH) strain is a newly established, polygenic mouse model for type 2 diabetes (T2D) and obesity, and we have previously reported some key physiological features of this model after the overt onset of diabetes. In the present work, we conducted a comprehensive phenotypic characterization of TH in order to completely characterize this new and relevant model for human T2D and obesity. We monitored the development of obesity and diabetes starting at 4 weeks of age by measuring body weight, glucose tolerance, and plasma levels of insulin, glucose, and triglyceride. Additionally, histological alterations in the pancreas and glucose uptake and glucose transporter 4 (GLUT4) content in soleus muscle were also examined. Compared with age-and sex-matched C57BL/6J (B6) mice, both male and female TH mice were significantly heavier, hyperleptinemic, and hyperinsulinemic at 4 weeks of age, without glucose intolerance or hyperglycemia. TH mice maintained higher body weights throughout the study period of 16 weeks. The hyperinsulinemia in TH mice worsened with age, but to a lesser degree in females than in males. Both the male and the female TH mice had enlarged pancreatic islets. Male TH mice showed impaired glucose tolerance at 8 weeks that became more prominent at 16 weeks. Plasma glucose levels continuously increased with age in male TH mice resulting in frank diabetes, while female TH mice remained normoglycemic throughout the study. Impaired glucose tolerance and hyperglycemia in male TH mice were accompanied by impaired 2-deoxyglucose uptake in the soleus muscle at basal and insulin-stimulated states, but without any reduction in GLUT4 content. Interestingly, male TH mice exhibited a drastic elevation in plasma triglyceride levels in the pre-diabetic stage that was maintained throughout the study. These findings suggest that obesity and insulin resistance are an inherent part of the TH phenotype and glucose intolerance is evident preceding progression to overt diabetes in male TH mice.

Wild-type reverse transcriptase has evolved for the survival of human immunodeficiency virus type 1 (HIV-1) by natural selection. In contrast, therapy relying on inhibitors of reverse transcriptase by nucleosides like zidovudine (AZT) or dideoxyinosine (ddI), and by non-nucleosides like pyridinones or nevirapine, may exert different selection pressures on this enzyme. Therefore the acquisition of resistance to reverse transcriptase inhibitors by selection of mutations in the pol gene may require compromises in enzyme function that affect viral replication. As single mutations are unlikely to confer broad resistance when combinations of reverse transcriptase inhibitors are used, multiple mutations may occur that result in further compromises. Certain drug combinations may prevent the co-existence of adequate reverse transcription function and multi-drug resistance (MDR). Unlike bacterial or eukaryotic drug resistance, retroviral drug resistance is conferred only by mutations in its own genome and is limited by genome size. Combining drugs directed against the same essential viral protein may thus prevent HIV-1 MDR, whereas the conventional approach of targeting different HIV-1 proteins for combination therapy may not, because genomes with resistance mutations in different HIV-1 genes might recombine to develop MDR. Here we show that several mutations in the HIV-1 reverse transcriptase gene that confer resistance to inhibitors of this enzyme can attenuate viral replication. We tested whether combinations of mutations giving rise to single-agent resistance might further compromise or even abolish viral replication, and if multidrug-resistant viruses could be constructed. Certain combinations of mutations conferring resistance to AZT, ddI and pyridinone are incompatible with viral replication. These results indicate that evolutionary limitations exist to restrict development of MDR. Furthermore, a therapeutic strategy exploiting these limitations by using selected multidrug regimens directed against the same target may prevent development of MDR. This approach, which we call convergent combination therapy, eliminated HIV-1 replication and virus breakthrough in vitro, and may be applicable to other viral targets. Moreover, elimination of reverse transcription by convergent combination therapy may also limit MDR.

Defective carbohydrate metabolism in mice homozygous for the tubby mutation.

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Interactions between HIV-1 and CMV may be important in the pathogenesis of AIDS. We have studied whether active CMV infection alters the cell tropism of HIV-1 in dually-infected individuals. Urines from HIV-seropositive individuals excreting CMV were compared to urines from CMV non-excretors. Sixty-six urines from HIV-seropositive individuals were tested. Infectious HIV-1 was not detected in any of the concentrated urines tested. The urines were filtered, concentrated, DNase-treated and cultured on HIV-1 non-permissive human forestin fibroblasts. HIV-1 DNA was detected by PCR with pol gene primers in 5 of 39 MRHF cell cultures inoculated with CMV culture positive urine (p = 0.037). HIV-1 DNA was not detected by PCR in uninfected fibroblasts, in fibroblasts inoculated with CMV uninfected urine from 27 HIV-seropositive patients or in fibroblasts cultured with 9 CMV culture positive urines from 16 HIV-seronegative renal transplant recipients. Supernatant fluid from an HIV-1 PCR-positive culture was passaged onto another fibroblast monolayer, and these cells were negative for HIV-1 DNA. Direct inoculation of fibroblasts with HIV-1 did not yield evidence of infection by PCR. CMV infection may facilitate HIV-1 DNA entry into ordinarily non-permissive cells.

Transient expression of HIV-1 p24 antigen was observed in eosinophils acutely infected with the HTLV-IIIB strain of HIV-1. PCR analysis of eosinophils isolated from 18 seropositive individuals showed HIV-1 sequences to be present in 2 subjects. These data suggest that eosinophils may act as host cells for HIV-1.