Potent inhibition of human immunodeficiency virus type 1 in primary T cells and alveolar macrophages by a combination anti-Rev strategy delivered in an adeno-associated virus vector.
The rate of viral replication appears to play a pivotal role in human immunodeficiency virus type 1 (HIV-1) pathogenesis and disease progression as it outstrips the capacity of the immune system to respond. Important cellular sites for HIV-1 production include T lymphocytes and tissue macrophages. Antiviral strategies, including newer treatment modalities such as gene therapy of HIV-1-susceptible cell populations, must be capable of engendering durable inhibitory effects to HIV-1 replication in both of these primary cell types in order to be effective. Among the potential genetic targets for intervention in the HIV-1 life cycle, the Rev regulatory system, consisting of Rev and its binding site, the Rev-responsive element (RRE), stands out as particularly attractive. Rev is essential for maintaining the stability of the viral genomic RNA as well as viral mRNAs encoding key structural and regulatory proteins. Moreover, it exhibits favorable threshold kinetics, in that Rev concentrations must rise above a critical level to exert their effect. To disable Rev function, primary T cells or macrophages were transduced with anti-Rev single-chain immunoglobulin (SFv) or RRE decoy genes either singly or in combination by employing adeno-associated virus vectors and then challenged with HIV-1. By directing both a protein and a nucleic acid against the normal interaction between Rev and the RRE, this genetic antiviral strategy effectively inhibited infection by either clinical or laboratory virus isolates. These results provide a framework for novel interventions to reduce virus production in the infected host.
Inouye
R T
RT
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine, Boston, Massachusetts 02215, USA.
Du
B
B
Boldt-Houle
D
D
Ferrante
A
A
Park
I W
IW
Hammer
S M
SM
Duan
L
L
Groopman
J E
JE
Pomerantz
R J
RJ
Terwilliger
E F
EF
D000163:Acquired Immunodeficiency Syndrome / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D015694:Gene Products, rev / Q000037:antagonists & inhibitors*; D015316:Genetic Therapy; D005822:Genetic Vectors; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016676:Macrophages, Alveolar / Q000821:virology*; D013601:T-Lymphocytes / Q000821:virology*; D014162:Transfection; D054321:rev Gene Products, Human Immunodeficiency Virus
D015694:Gene Products, rev; D054321:rev Gene Products, Human Immunodeficiency Virus