Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects.
We have genetically engineered CD4(+) and CD8(+) T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4zeta, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (zeta) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 x 10(10) autologous CD4zeta-modified CD4(+) and CD8(+) T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/microL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4zeta was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue-associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4zeta T cells. CD4(+) counts increased by 73/microL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.
University of California, Los Angeles, USA.
R T
RT
Mitsuyasu
P A
PA
Anton
S G
SG
Deeks
D T
DT
Scadden
E
E
Connick
M T
MT
Downs
A
A
Bakker
M R
MR
Roberts
C H
CH
June
S
S
Jalali
A A
AA
Lin
R
R
Pennathur-Das
K M
KM
Hege
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000628:therapy*; D019264:Adoptive Transfer / Q000009:adverse effects; D000328:Adult; D015704:CD4 Antigens / Q000235:genetics* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002465:Cell Movement; D002470:Cell Survival; D005260:Female; D018014:Gene Transfer Techniques; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D014182:Transplantation, Autologous
D015704:CD4 Antigens