Long-term survival and concomitant gene expression of ribozyme-transduced CD4+ T-lymphocytes in HIV-infected patients.
BACKGROUND
An anti-HIV-1 tat ribozyme, termed Rz2, has been shown to inhibit HIV-1 infection/replication and to decrease HIV-1-induced pathogenicity in T-lymphocyte cell lines and normal peripheral blood T-lymphocytes. We report here the results of a phase I gene transfer clinical trial using Rz2.


METHODS
Apheresis was used to obtain a peripheral blood cell population from each of four HIV-negative donors. After enrichment for CD4+ T-lymphocytes, ex vivo expansion and genetic manipulation (approximately equal aliquots of the cells were transduced with the ribozyme-containing (RRz2) and the control (LNL6) retroviral vector), these cells were infused into the corresponding HIV-1-positive twin recipient. Marking was assessed over an initial 24-week period and in total over an approximate 4-year period.


RESULTS
The gene transfer procedure was shown to be safe, and technically feasible. Both RRz2- and LNL6-gene-containing peripheral blood mononuclear cells (PBMC) were detected at all time points examined to 4 years. There was concomitant gene construct expression in the absence of the need for ex vivo peripheral blood cell stimulation and there was no evidence of immune elimination of the neoR T-lymphocytes nor of silencing of the Moloney murine leukemia virus long terminal repeat.


CONCLUSIONS
The proof of principle results reported here demonstrate safety and feasibility of this type of gene transfer approach. While not specifically tested, T-lymphocytes containing an anti-HIV gene construct may impact on HIV-1 viral load and CD4+ T-lymphocyte count, potentially representing a new therapeutic modality for HIV-1 infection.
Macpherson
Janet L
JL
Johnson and Johnson Research Pty Limited, Locked Bag 4555, Strawberry Hills, Sydney, NSW Australia 2012. jmacpher@medau.jnj.com
Boyd
Maureen P
MP
Arndt
Allison J
AJ
Todd
Alison V
AV
Fanning
Gregory C
GC
Ely
Julie A
JA
Elliott
Fiona
F
Knop
Alison
A
Raponi
Mitch
M
Murray
John
J
Gerlach
Wayne
W
Sun
Lun-Quan
LQ
Penny
Ronald
R
Symonds
Geoff P
GP
Carr
Andrew
A
Cooper
David A
DA
D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004200:Diseases in Twins / Q000276:immunology / Q000628:therapy*; D015870:Gene Expression; D015756:Genes, tat / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D015658:HIV Infections / Q000276:immunology / Q000628:therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D016337:RNA, Catalytic / Q000235:genetics / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D015996:Survival Rate; D013997:Time Factors; D014161:Transduction, Genetic; D014430:Twins, Monozygotic
D016337:RNA, Catalytic