Cytomegalovirus vectors enabling control of t cell targeting

Abstract

Disclosed herein are CMV vectors that include a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), an active UL128 protein (or ortholog thereof), but wherein the CMV vector lacks an active UL130 protein (or an ortholog thereof). Also disclosed herein are CMV vectors comprising: a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), an active UL130 protein (or an ortholog thereof), but wherein the CMV vector lacks an active UL128 protein. Further disclosed are methods of using CMV vectors to generate an immune response characterized as having at least 10% of the CD8+ T cells directed against epitopes presented by MHC Class II.

1 - 18 . (canceled) 
     
     
         19 . A human cytomegalovirus (CMV) vector comprising:
 (i) a first nucleic acid sequence that encodes a heterologous protein antigen, a second nucleic acid sequence that encodes UL128, and a third nucleic acid sequence that encodes UL131, wherein the vector comprises a mutation in UL130 selected from a point mutation, a frameshift mutation, or a deletion of all or less than all of UL130 and does not express an active UL130 protein; or   (ii) a first nucleic acid sequence that encodes an heterologous protein antigen, a second nucleic acid sequence that encodes UL130, and a third nucleic acid sequence that encodes UL131, wherein the vector comprises a mutation in UL128 selected from a point mutation, a frameshift mutation, or a deletion of all or less than all of UL128 and does not express an active UL128 protein.   
     
     
         20 . The vector of  claim 19 , wherein the heterologous antigen comprises a pathogen specific antigen. 
     
     
         21 . The vector of  claim 20 , wherein the pathogen specific antigen is derived from a human immunodeficiency virus. 
     
     
         22 . The vector of  claim 20 , wherein the pathogen specific antigen is derived from  Mycobacterium tuberculosis.    
     
     
         23 . The vector of  claim 19 , wherein the heterologous antigen comprises a cancer antigen. 
     
     
         24 . The vector of  claim 23 , wherein the cancer antigen is a prostate cancer antigen. 
     
     
         25 . A method of generating a CD8+ T cell response to a heterologous antigen in a subject, the method comprising administering the vector of  claim 19  to the subject. 
     
     
         26 . The method of  claim 25 , wherein at least 10% of the CD8+ T cell response to the heterologous antigen is directed against epitopes presented by MEW Class II. 
     
     
         27 . The method of  claim 25 , wherein the response comprises at least 50% Class II restricted CD8+ epitopes. 
     
     
         28 . The method of  claim 25 , wherein the subject has been previously exposed to CMV. 
     
     
         29 . The method of  claim 25 , wherein administering comprises intravenous, intramuscular, intraperitoneal, or oral administration of the vector. 
     
     
         30 . The method of  claim 25 , further comprising administering a second CMV vector comprising a third nucleic acid sequence encoding a second heterologous antigen to the subject. 
     
     
         31 . The method of  claim 30 , wherein the second CMV vector encodes an active UL128 protein and an active UL130 protein. 
     
     
         32 . The method of  claim 31 , wherein the first heterologous antigen and the second heterologous antigen are the same antigen. 
     
     
         33 . The method of  claim 32 , wherein the heterologous antigen comprises a pathogen specific antigen. 
     
     
         34 . The method of  claim 33 , wherein the pathogen specific antigen is derived from a human immunodeficiency virus. 
     
     
         35 . The method of  claim 33 , wherein the pathogen specific antigen is derived from  Mycobacterium tuberculosis.    
     
     
         36 . The method of  claim 32 , wherein the heterologous antigen comprises a cancer antigen. 
     
     
         37 . The method of  claim 36 , wherein the cancer antigen is a prostate cancer antigen. 
     
     
         38 . The method of  claim 30 , wherein the second CMV vector is administered before, concurrently with, or after the first CMV vector.