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Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay
Published on: September 14, 2014
Sensitivity of HIV type 1 primary isolates to human anti-CD40 antibody-mediated suppression is related to coreceptor
Sisay A Abayneh1, Peter Ellmark, Ulf Karlsson
1Division of Medical Microbiology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Abstract:
The effect of CD40 ligation on infection by HIV-1 primary isolates with different R5 phenotypes was evaluated with a novel set of anti-CD40 monoclonal antibodies originating from a human phage display library. Five human monoclonal anti-CD40 antibodies of IgG1 subtype characterized by the ability to activate B cells via CD40 were tested for induction of the CC-chemokines RANTES and MIP-1alpha and inhibition of HIV-1 replication in primary monocyte-derived macrophages (MDM). All activating anti-CD40 antibodies were able to induce CC-chemokines in MDM. We chose the most potent antibody, clone B44, for further experiments. This antibody had a suppressive effect on HIV-1 isolates of the R5 phenotype with limited use of CCR5/CXCR4 chimeric receptors. In comparison, HIV-1 isolates with broader use of CCR5/CXCR4 chimeric receptors or with CXCR4 use were less sensitive to anti-CD40-induced suppression. The results indicate that HIV-1 replication is inhibited by human anti-CD40 monoclonal antibodies through the mechanism of CC-chemokine induction. This effect is thus restricted to HIV-1 isolates sensitive to inhibition by CC-chemokines.
Insights
Novel human anti-CD40 antibodies inhibit HIV-1 replication in macrophages by inducing CC-chemokines. This antiviral effect is specific to HIV-1 strains sensitive to CC-chemokine-mediated suppression.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- Human immunodeficiency virus type 1 (HIV-1) infection remains a significant global health challenge.
- Understanding host-pathogen interactions and identifying novel therapeutic targets are crucial for controlling HIV-1.
- CD40 ligation is known to modulate immune responses, but its specific effects on HIV-1 replication require further elucidation.
Purpose of the Study:
- To evaluate the impact of CD40 ligation using novel human monoclonal antibodies on HIV-1 replication in primary cells.
- To investigate the role of CC-chemokines, such as RANTES and MIP-1alpha, in mediating the antiviral effects of anti-CD40 antibodies.
- To determine the susceptibility of different HIV-1 primary isolates, based on their coreceptor usage (CCR5/CXCR4), to anti-CD40 antibody-induced suppression.
Main Methods:
- Utilized a panel of five human monoclonal anti-CD40 antibodies derived from a phage display library.
- Assessed the ability of these antibodies to activate B cells and induce CC-chemokine production (RANTES, MIP-1alpha) in primary monocyte-derived macrophages (MDM).
- Tested the inhibitory effect of the most potent anti-CD40 antibody (clone B44) on the replication of various HIV-1 primary isolates with differing R5 phenotypes and coreceptor usage patterns.
Main Results:
- All tested activating anti-CD40 antibodies successfully induced CC-chemokines in MDM.
- The potent anti-CD40 antibody, clone B44, demonstrated a significant suppressive effect on HIV-1 isolates utilizing primarily CCR5 (R5 phenotype) with limited use of CCR5/CXCR4 chimeric receptors.
- HIV-1 isolates with broader CCR5/CXCR4 chimeric receptor use or exclusive CXCR4 use exhibited reduced sensitivity to the suppressive effects of anti-CD40 antibody treatment.
Conclusions:
- Human anti-CD40 monoclonal antibodies can inhibit HIV-1 replication in macrophages.
- The mechanism of inhibition is linked to the induction of CC-chemokines, such as RANTES and MIP-1alpha.
- The antiviral efficacy of anti-CD40 antibodies is dependent on the specific HIV-1 isolate's sensitivity to CC-chemokine-mediated suppression, particularly affecting R5-tropic strains.
