Mutation multiple

Resistance occurs by mutations (multiple) in the gene that codes for RT. 

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

The blastocyst is an early embryonic stage in mammalian development. Murine blastocysts can be harvested at day 3.5 p.c. Their inner cell mass contains embryonic stem cells. Multiple murine embryonic stem cell lines have been established. Embryonic stem cells carrying genetically engineered mutations are injected into blastocysts, which are subsequently implanted into pseudopregnant foster mothers. 

Multiple channelopathies resulting from mutations in Kir channels are known. 

It can be expected that the requirement to accumulate multiple mutations to generate a resistant phenotype may translate into a relatively slow development of clinical HCMV resistance, hi addition, a mechanism that is distinct from those of the marketed drugs will offer the possibility of treating patients who have acquired resistance to these agents. 

CCR5 expression likely plays a role in T-cell recruitment and may be involved in the development of autoimmune diseases. There is a negative association between the CCR5A32 mutation and rheumatoid arthritis (Prahalad 2006). Furthermore, additional studies reviewed elsewhere suggest the involvement of CCR5 in multiple sclerosis, diabetes, and transplant rejection (Ribeiro and Horuk 2005). As such, it is likely that CCR5 antagonists developed for the treatment of HIV-1 infection can also be used for other diseases. 

A second mechanism of resistance involves alterations in PBPs which affect binding of /3-lactams. These changes have been found to occur by multiple substitutions through recombination rather than point mutations. Acquired penicillin resistance in Strep, pneumoniae is because of such gene mosaics which code for an altered yet functional PBP with reduced affinity for penicillin. Sections of the susceptible PBP gene have been replaced by other DNA sequences, presumably via transformation. 

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