METHODS AND COMPOSITIONS FOR TREATING HIV
The invention features nucleic acid constructs encoding chimeric immune T-Cell receptors (CIRs) that are useful for treating HIV in patients. In general, the CIRs contain an extracellular domain which targets HIV or HIV infected cells (e.g., the extracellular domain of CD4), a transmembrane domain, and a cytoplasmic domain for mediating T-Cell activation (e.g. CD3 zeta and/or the partical extracellular domain of CD28). The invention also features the use of host cells expressing CIRs in the treatment of HIV.
1 . A nucleic acid construct encoding a chimeric protein comprising
(i) an extracellular domain of CD4, or a fragment thereof,
(ii) a transmembrane domain, and
(iii) a cytoplasmic domain comprising
a) the cytoplasmic domain of the CD3 zeta chain, or a fragment thereof and
b) the cytoplasmic domain of CD28, or a fragment thereof.
2 . The nucleic acid construct of claim 1 , wherein said chimeric protein is capable of forming a homodimer when expressed in a T cell.
3 . The nucleic acid construct of claim 2 , wherein the dimerized chimeric proteins are capable of forming at least one disulfide bond.
4 . The nucleic acid construct of claim 1 , wherein said transmembrane domain comprises a polypeptide selected from the group consisting of the transmembrane domain of the CD3 zeta chain and the transmembrane domain of CD28.
5 . The nucleic acid construct of claim 4 , wherein said transmembrane domain comprises amino acids 7-30 of SEQ 10 NO:3.
6 . (canceled)
7 . The nucleic acid construct of claim 1 , wherein said extracellular domain of CD4 comprises amino acids 1-372 of SEQ 10 NO:1.
8 . The nucleic acid construct of claim 1 , wherein said cytoplasmic domain of the CD3 zeta chain comprises amino acids 31-142 of SEQ 10 NO:3.
9 . The nucleic acid construct of claim 1 , wherein said cytoplasmic domain of CD28 comprises amino acids 127-234 of SEQ 10 NO:2.
10 . The nucleic acid construct of claim 1 , wherein said cytoplasmic domain comprises the amino acid sequence of SEQ ID NO:10.
11 . A nucleic acid construct encoding a chimeric protein comprising
(i) an extracellular domain of CD4, or a fragment thereof,
(ii) a transmembrane domain, and
(iii) a cytoplasmic domain of the CD3 zeta chain, or a fragment thereof, wherein said chimeric protein is capable of forming a homodimer when expressed in a T cell.
12 . The nucleic acid construct of claim 11 , wherein the chimeric protein, when in a homodimer, is capable of forming at least one disulfide bond with the chimeric protein with which it is dimerized.
13 . The nucleic acid construct of claim 11 , wherein said transmembrane domain comprises the transmembrane domain of the CD3 zeta chain or the transmembrane domain of CD28.
14 . The nucleic acid construct of claim 13 , wherein said transmembrane domain comprises amino acids 7-30 of SEQ ID NO:3.
15 . (canceled)
16 . The nucleic acid construct of claim 11 , wherein said extracellular domain of CD4 comprises amino acids 1-372 of SEQ ID NO:1.
17 . The nucleic acid construct of claim 11 , wherein said cytoplasmic domain of the CD3 zeta chain comprises amino acids 31-142 of SEQ ID NO:3.
18 . (canceled)
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . A host cell comprising the nucleic acid construct of claim 1 and a nucleic acid construct encoding an siRNA.
26 . The host cell of claim 25 , wherein said siRNA is against CCR5.
27 . The host cell of claim 25 , wherein said siRNA is against Tat/Rev.
28 . A method of treating a patient infected with HIV by administering a composition comprising host cell of claim 22 .
29 . (canceled)