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Lentiviral vectors interfering with virus-induced CD4 down-modulation potently block human immunodeficiency virus
Hang M Pham1, Enrique R Argañaraz, Bettina Groschel
1La Jolla Institute for Molecular Medicine, 4570 Executive Dr., Suite 100, San Diego, CA 92121, USA.
Abstract:
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.
Insights
New HIV vectors deliver CD4 molecules resistant to viral down-modulation, significantly reducing infectious particle production. This approach offers a novel therapeutic strategy against HIV by targeting viral pathogenesis.
Area of Science:
- Virology
- Immunology
- Gene Therapy
Background:
- CD4 down-modulation is critical for human immunodeficiency virus (HIV) infectious particle production.
- Enhanced viral-induced CD4 down-modulation correlates with disease progression.
- Viruses defective in CD4 down-modulation are found in long-term nonprogressors.
Purpose of the Study:
- To develop HIV-based vectors delivering CD4 molecules resistant to viral Nef and Vpu down-modulation.
- To evaluate the efficacy of these vectors in blocking HIV-1 infectivity and replication.
Main Methods:
- Constructed HIV-based vectors encoding truncated CD4 molecules resistant to Nef and Vpu.
- Transduced cells with these vectors and assessed viral particle production and infectivity.
- Tested lentiviral vectors in various cell lines and primary lymphocytes.
Main Results:
- Transduced cells produced viral particles normally, but infectivity was reduced 1,000-fold.
- Lentiviral vectors efficiently blocked HIV-1 infectivity and replication.
- Demonstrated proof-of-principle for targeting virus-induced CD4 down-modulation.
Conclusions:
- Targeting virus-induced CD4 down-modulation is a viable strategy for novel anti-HIV therapies.
- HIV-based vectors expressing resistant CD4 molecules offer a promising therapeutic approach.
