Inhibition of human immunodeficiency virus replication and growth advantage of CD4+ T cells from HIV-infected individuals that express intracellular antibodies against HIV-1 gp120 or Tat.
Current clinical gene therapy protocols for the treatment of human immunodeficiency virus type 1 (HIV-1) infection often involve the ex vivo transduction and expansion of CD4+ T cells derived from HIV-positive patients at a late stage in their disease (CD4 count <400). These protocols involve the transduction of T cells by murine leukemia virus (MLV)-based vectors encoding antiviral constructs such as the rev m10 dominant negative mutant or a ribozyme directed against the CAP site of HIV-1 RNA. We examined the efficiency and stability of transduction of CD4+ T cells derived from HIV-infected patients at different stages in the progression of their disease, from seroconversion to AIDS. CD4+ T cells from HIV-positive patients and uninfected donors were transduced with MLV-based vectors encoding beta-galactosidase and an intracellular antibody directed against gp120 (sFv 105) or Tat. (sFvtat1-Ckappa). The expression of marker genes and the effects of the antiviral constructs were monitored in vitro in unselected transduced CD4+ T cells. Efficiency and stability of transduction varied during the course of HIV infection; CD4+ T cells derived from asymptomatic patients were transducible at higher efficiencies and stabilities than CD4+ T cells from patients with acquired immunodeficiency syndrome (AIDS). Expression of the anti-tat intracellular antibody was more effective at stably inhibiting HIV-1 replication in transduced cells from HIV-infected individuals than was sFv 105. The results of this study have important implications for the development of a clinically relevant gene therapy for the treatment of HIV-1 infection.
Poznansky
M C
MC
The Dept. of Genito-Urinary Medicine and Communicable Diseases, Imperial College School of Medicine at St. Mary's, London, UK.
Foxall
R
R
Mhashilkar
A
A
Coker
R
R
Jones
S
S
Ramstedt
U
U
Marasco
W
W
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology*; D002455:Cell Division; D015696:Gene Products, tat / Q000276:immunology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics; D051379:Mice; D014779:Virus Replication / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D054322:tat Gene Products, Human Immunodeficiency Virus