**6. Conclusions**

The comparison of the MV genomic sequence corresponding to Madrid SSPE cases SMa79, SMa84, and SMa94 with those of MV genotypes circulating in Madrid during the last 5 decades provided the first confirmation that the MV causing SSPE corresponds to the virus producing the measles acute infection and not to a possible re-infection years later at onset of the encephalitis. This was the first example of a human persistent infection by an RNA virus.

2. Concerning the question of where the virus could persist and replicate during the long latent period, we have observed that at least in the final stages of SSPE, MV is also present in abdominal and thoracic lymph nodes. The comparison of MV genomic RNA from brain and lymph nodes for each patient showed both viruses belong to the same genotype.

3. In two SSPE cases, those presenting an average and long disease course, but not in the short disease course case, biased hypermutation U to C was observed in the matrix M gene at a high level (38% U to C) and low level (10%U to C) respectively. The mutation map across the entire genome was the same from distant parts of each brain, supporting the indication of clonal origin of MV brain invasion proposed by V. ter Meulen, M. Billeter and collaborators. After the first decription of biased U to C hypermutation phenomena by M.Billeter and collaborators in one brain from a MIBE case, our results were the first description of biased hypermutation in SSPE brain. Our results indicate that biased hypermutation U to C are found at autopsia in brain of SSPE patients after years of disease, and it is not proportional to the length of the disease. Biased hypermutation U to C is present in MV localized in lymph nodes at similar or higher level than in the respective brain, suggesting that biased hypermutation may take place also in infected lymphoid cells. In the three cases the transcription of M, F and H genes were down-regulated, and M protein ability to bind to MV nucleocapsids was impaired by deletion or biased hypermutation.

4. The length of MV genome found in the brain of SSPE remains constant, 15894 after years to decades of persitent infection, and no evidence of significant proportion of nucleocapsid subgenomic RNAs was found in the brains of the SSPE cases studied. Copy-back subgenomic RNAs were found in MV nucleocapsids only in one of the three brains, indicating that the presence of MV defective interfering particles is not an universal feature in SSPE.

5. Currently, no efficient treatment for SSPE o MIBE patients is available. New approaches to therapy of these lethal encephalitis are underway in several laboratories, and possibly the future treatments will combine several therapies to control MV infection by specific antiviral designed drugs and molecules that would counteract virus escape to host immune response. Today, the only effective way to prevent MV encephalitis is the implementation of measles vaccination programs.
