Subject viral

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

Interim results from the SPRINT-1 phase 2 trial of boceprevir (SCH 503034) have been released. In subjects who received boceprevir plus interferon-a and ribavirin, viral RNA loads were suppressed at week 12 in between 70 and 79% of subjects infected with genotype 1 HCV, compared with only 34% in the interferon-o/ ribavirin standard of care arm (www.sch-plough.com/schering plough/news/release. jsp releaseID = 1064540). However, it is not yet known if this enhanced early response will translate into sustained response. 

Currently, treatment of DSP and ATN is similar to many other neuropathies that have predominantly painful sensory involvement (Mendell and Sahenk 2003 Gonzalez-Duarte et al. 2007). It is purely symptomatic as there are no proven regenerative therapies to reverse the underlying process. An 8-month prospective pilot study reported an improvement in subjective quantitative sensory testing (QST) in HIV-infected patients who responded to HAART (Martin et al. 2000). The patients who did not respond to HAART did not show any improvements in QST. It is possible that suppression of viral load will slow the progression of DSP. Some studies have found a correlation between viral load and incidence (Childs et al. 1999), or severity (Simpson et al. 2002) of sensory neuropathy. Others, however, did not find any correlation between plasma viral loads and incidence of DSP or ATN (Brew et al. 2003). 

In the region with pesticide contamination where subjects contracted viral hepatitis A, the pre-jaundice period was 4.2 days (in the control area, 5.1), the jaundice period lasted 32 days (22.4 in the control area), the liver enlarged more than in the control area and took longer to return to normal size, there was a larger number of patients who also had an enlarged spleen, there was more frequent damage to the nervous and cardiovascular systems (1.5-2 times higher than in the control area), mixed syndrome was observed more often (45% of the time, compared to 12.6% in the control area), and the illness was more frequently serious. 

Biopharmaceutical products are also subjected to screening for the presence of viral particles prior to final product release. Although viruses could be introduced, for example, via infected personnel during downstream processing, proper implementation of GMP minimizes such risk. Any viral particles found in the finished product are most likely derived from raw material sources. Examples could include HIV or hepatitis viruses present in blood used in the manufacture of blood products. Such raw materials must be screened before processing for the presence of likely viral contaminants. 

The stress-associated shift in Thl/Th2 cytokines observed in human subjects has also been demonstrated in restraint-stressed mice. Associated with the shift towards a Th2 response are a significant decrease in NK cell activity, decreased IFN-y production by Con A-stimulated splenocytes, and a concomitant increase in serum corticosterone levels after 24 hours of restraint.30 These observations are consistent with studies on the effects of restraint stress and the immune response to viral infection. Restraint-stressed mice exhibited a decline in NK cell activity and a decrease in the generation of virus-specific cytotoxic T lymphocytes to HSV-l after primary infection, which resulted in an increase in the replication of the virus at the site of infection.3132... 

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