Lentiviral vectors interfering with virus-induced CD4 down-modulation potently block human immunodeficiency virus type 1 replication in primary lymphocytes.
CD4 down-modulation is essential for the production of human immunodeficiency virus (HIV) infectious particles. Disease progression correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. Despite multiple pieces of evidence highlighting the importance of this function in viral pathogenesis in vivo, to date, HIV-induced CD4 down-modulation has not been used as a target for intervention. We describe here HIV-based vectors that deliver truncated CD4 molecules resistant to down-modulation by the viral products Nef and Vpu. Infection of cells previously transduced with these vectors proceeded normally, and viral particles were released in normal amounts. However, the infectivity of the released virions was reduced 1,000-fold. Lentiviral vectors expressing truncated CD4 molecules were efficient at blocking HIV-1 infectivity and replication in several cell lines and in CD4-positive primary lymphocytes. The findings presented here provide proof-of-principle that approaches targeting the virus-induced CD4 down-modulation may constitute the basis for novel anti-HIV therapies.
Pham
Hang M
HM
La Jolla Institute for Molecular Medicine, 4570 Executive Dr., Suite 100, San Diego, CA 92121, USA.
Argañaraz
Enrique R
ER
Groschel
Bettina
B
Trono
Didier
D
Lama
Juan
J
D015704:CD4 Antigens / Q000032:analysis*; D015536:Down-Regulation; D015693:Gene Products, nef / Q000502:physiology; D005822:Genetic Vectors / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D008214:Lymphocytes / Q000821:virology*; D054334:Viral Regulatory and Accessory Proteins / Q000502:physiology; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus; D000086082:Viroporin Proteins
D015704:CD4 Antigens; D015693:Gene Products, nef; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins