In this article we report meta-analyses of the relation of attributional styles to depression. In 104 studies involving nearly 15,000 subjects, several attributional patterns had reliable associations with depression scores. For negative events, attributions to internal, stable, and global causes had a reliable and significant association with depression. Studies in which the attribution factors of ability and luck were measured also showed a reliable association with depression. For positive events, attributions to external, unstable, and specific causes were associated with depression. Ability and luck attribution factors for positive events were also associated with depression. The relations for positive events, however, were weaker than the corresponding ones for negative events. In general, these patterns of relations were independent of a number of potential mediators suggested by authors in this literature, including the type of subject studied (psychiatric vs. college student), the type of event about which the attribution is made (real vs. simulated), the depression measure used, or the publication status of the research report. These conclusions are compared with those of other reviews. Implications for attributional models of depression are discussed.

The mechanism of inhibition of HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues. Pre-steady-state kinetic analysis was used to establish the mechanism of inhibition by these noncompetitive inhibitors. Analysis of the pre-steady-state burst of DNA polymerization indicated that inhibitors blocked the chemical reaction, but did not interfere with nucleotide binding or the nucleotide-induced conformational change. Rather, in the presence of saturating concentrations of the inhibitors, the nucleoside triphosphate bound tightly (Kd, 100 nM), but nonproductively. The data suggest that an inhibitor combining the functionalities of a nonnucleoside inhibitor and a nucleotide analog could bind very tightly and specifically to reverse transcriptase and could be effective in the treatment of AIDS.

Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.

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To examine the role of the mitochondrial polymerase (Pol ␥) in clinically observed toxicity of nucleoside analogs used to treat AIDS, we examined the kinetics of incorporation catalyzed by Pol ␥ for each Food and Drug Administration-approved analog plus 1-(2-deoxy-2-fluoro-␤-D-arabinofuranosyl)-5-iodouracil (FIAU), ␤-L-(؊)-2,3-dideoxy-3-thiacytidine (؊)3TC, and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). We used recombinant exonuclease-deficient (E200A), reconstituted human Pol ␥ holoenzyme in single turnover kinetic studies to measure K d (K m ) and k pol (k cat ) to estimate the specificity constant (k cat /K m ) for each nucleoside analog triphosphate. The specificity constants vary more than 500,000-fold for the series ddC > ddA (ddI) > 2,3-didehydro-2,3-dideoxythymidine (d4T) > > (؉)3TC > > (؊)3TC > PMPA > azidothymidine (AZT) > > Carbovir (CBV). Abacavir (prodrug of CBV) and PMPA are two new drugs that are expected to be least toxic. Notably, the higher toxicities of d4T, ddC, and ddA arose from their 13-36-fold tighter binding relative to the normal dNTP even though their rates of incorporation were comparable with PMPA and AZT. We also examined the rate of exonuclease removal of each analog after incorporation. The rates varied from 0.06 to 0.0004 s ؊1 for the series FIAU > (؉)3TC ϳ (؊)3TC > CBV > AZT > PMPA ϳ d4T > > ddA (ddI) > > ddC. Removal of ddC was too slow to measure (<0.00002 s ؊1 ). The high toxicity of dideoxy compounds, ddC and ddI (metabolized to ddA), may be a combination of high rates of incorporation and ineffective exonuclease removal. Conversely, the more effective excision of (؊)3TC, CBV, and AZT may contribute to lower toxicity. FIAU is readily extended by the next correct base pair (0.13 s ؊1 ) faster than it is removed (0.06 s ؊1 ) and, therefore, is stably incorporated and highly mutagenic. We define a toxicity index for chain terminators to account for relative rates of incorporation versus removal. These results provide a method to rapidly screen new analogs for potential toxicity.Current treatment of HIV 1 includes a mixture that generally consists of a combination of nucleoside and nonnucleoside analogs directed against HIV RT, plus an inhibitor of HIV protease. Treatment with this mixture allows patients to coexist with a low level of virus for years, but treatments are limited by the development of resistance of HIV to the drugs on the one hand and toxicity of nucleoside analogs on the other. Toxicity of nucleoside analogs is particularly troublesome for the long term management of the viral infection. Nucleoside analogs function as chain terminators to suppress viral replication by HIV-1 RT, and because HIV RT lacks a proofreading exonuclease, the specificity of nucleoside analogs toward HIV RT results from selective discrimination during incorporation and/or from removal by the proofreading exonuclease of the host DNA polymerase.Six nucleoside analogs have received Food and Drug Administration approval for treatment of HIV, and these analogs are illustrated with others...