The effects of HHV-8 vMIP-II on SIVmac251 infection and replication competent and incompetent SIVmac239Delta3 vectors.
Human herpesvirus type 8 vMIP-II has one of the broadest ranges of chemokine receptor binding and therefore a multiplicity of biologic effects, both immunologic and antiviral. These properties make vMIP-II an attractive effector gene to be expressed from gene therapy vectors. The present studies were concerned with both therapeutic approaches: (1) an anti-simian immunodeficiency virus (SIV) biologic, and (2) an effector gene in SIV-based vectors. Regarding its antiviral properties, vMIP-II expressed from bacteria and SIV-based vectors bound the surface of CEMx174 cells and specifically suppressed SIVmac251 infection. A CCR3 monoclonal antibody partially inhibited vMIP-II binding, suggesting that both SIVmac251 and vMIP-II utilize a similar CCR3-like receptor for CEMx174 cell binding. Replication competent SIV-based vectors containing forward and reverse vMIP-II produced neither identifiable vMIP-II nor virions for the first 21 days. Virus replication occurred after this period. Significant sequence alterations in the forward vMIP-II containing replication competent vector transcripts were responsible for the failure of vMIP-II expression. The genetic basis for the initial failure to replicate virus and its later restoration was not determined but appeared in the II-PIMv containing vectors to coincide with deletions and compensatory rearrangements in nef 3' of the polypurine tract. Cells transfected with SIVmac239Delta3DeltaLTR-vMIP-II vectors expressed biologically active vMIP-II that bound CEMx174 cells and suppressed SIVmac251 infection. These data suggest that replication defective SIV vectors expressing immunobiolgic genes such as vMIP-II may prove useful in gene therapies, particularly in augmenting immune responses in chronically infected individuals.
Morris
Kevin V
KV
Department of Medicine 0678, Stein Clinical Research Building, Room 402, University of California, La Jolla, San Diego, CA 92093-0678, USA. kvmorris@ucsd.edu
Higgins
Joanne
J
Shen
Xiaoyng
X
Stine
Jonny T
JT
Pedersen
Niels C
NC
D019380:Anti-HIV Agents; D001483:Base Sequence; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004274:DNA, Recombinant; D005822:Genetic Vectors; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000737:chemistry; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D014764:Viral Proteins / Q000032:analysis / Q000096:biosynthesis; D014779:Virus Replication
D019380:Anti-HIV Agents; D018925:Chemokines; D004274:DNA, Recombinant; D012367:RNA, Viral; D019707:Receptors, Chemokine; D014764:Viral Proteins; C108059:vMIP-II