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Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 15, 2010
Interferon induction by HIV glycoprotein 120: role of the V3 loop
H Ankel1, M R Capobianchi, C Castilletti
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee 53226.
Insights
HIV-1
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Human Immunodeficiency Virus type 1 (HIV-1) infection can trigger immune responses.
- Interferon (IFN) induction is a key component of the innate immune system.
- Peripheral blood mononuclear cells (PBMC) are crucial in immune responses to viral infections.
Purpose of the Study:
- To elucidate the mechanism by which HIV-1 induces IFN in PBMC.
- To identify the viral and cellular components involved in IFN induction by HIV-1.
Main Methods:
- Utilized recombinant HIV-1 gp120 glycoproteins from different strains (HIVIIIB and MN) as potential inducers.
- Employed monoclonal antibodies (mABs) targeting specific domains of gp120 and CD4.
- Investigated the inhibitory effects of mABs and V3-homologous peptides on IFN induction.
Main Results:
- HIVIIIB-derived gp120 induced IFN in PBMC, while MN-derived gp120 did not.
- Antibodies blocking gp120-CD4 binding or targeting the CD4 hinge region abolished IFN induction.
- Antibodies against the HIV-1 V3 loop and V3-homologous peptides also inhibited IFN induction.
Conclusions:
- HIV-1 gp120 binding to CD4 initiates a conformational change, positioning the V3 loop.
- Interaction of the V3 loop with a putative secondary receptor on PBMC triggers IFN induction.
- This mechanism highlights a novel pathway for viral-mediated immune activation by HIV-1.
Abstract:
We have studied the mechanism of IFN induction by HIV-1 in peripheral blood mononuclear cells (PBMC), using recombinant viral membrane glycoproteins as potential inducers. Whereas 8 nM HIVIIIB-derived gp120 resulted in IFN levels between 80 and 2000 IU/ml with PBMC from different donors, gp120 from the MN strain was not an inducer. Preincubation of HIVIIIB-gp120 with a monoclonal antibody (mAB) to its CD4 binding domain or of PBMC with a mAB to the gp120 binding domain of CD4 abolished IFN induction. Antibodies against the third extracellular domain of CD4 which did not block binding of gp120, however, were also inhibitory. Furthermore, several mABs to the third variable loop (V3) of HIVIIIB-gp120 also blocked IFN induction, suggesting an important role of V3 in this process. This was further supported by the inhibitory action of peptides homologous to complete or partial sequences of V3. We conclude that after binding of gp120 to its CD4 receptor the V3 loop can be positioned close to the membrane of the responder cells by bending of gp120-occupied CD4 at its hinge region between extracellular domains 2 and 3. As a result V3 is able to interact with a V3-specific "secondary receptor" on the membranes of these cells. We suggest that it is the latter interaction which triggers IFN induction.
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