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Reactivity profiles of broadly neutralizing anti-HIV-1 antibodies are distinct from those of pathogenic autoantibodies.

ABSTRACT: Broadly neutralizing antibodies (bNt Abs) against HIV-1 are rarely produced during natural infection, and efforts to induce such Abs by vaccination have been unsuccessful. Thus, elucidating the nature and cellular origins of bNt Abs is a high priority for vaccine research. As the bNt monoclonal Abs (MAbs) 2F5, 4E10 and 2G12 have been reported to bind select autoantigens, we investigated whether these MAbs display a broader range of autoreactivity and how their autoreactivity compares with that of pathogenic autoAbs.An autoantigen microarray comprising 106 connective tissue disease-related autoantigens and control antigens was developed and used, in combination with ELISAs, to compare the reactivity profiles of MAbs 4E10, 2F5 and 2G12 to those of four pathogenic autoAbs derived from patients with antiphospholipid-syndrome (APS), and to serum from a patient with systemic lupus erythematosus (SLE).The APS MAbs and SLE serum reacted strongly with multiple autoantigens on the microarray, whereas anti-HIV-1 MAb reactivity was limited mainly to HIV-1-related antigens. The APS autoAbs reacted strongly with CL, yet only 4E10 bound CL at high concentrations; both 2F5 and 4E10 bound their HIV-1 epitopes with a 2-3-log higher apparent affinity than CL. Moreover, the polyreactivity of 4E10, but not CL15, could be blocked with dried milk.The reactivity profiles of bNt anti-HIV-1 MAbs are fundamentally distinct from those of pathogenic autoAbs that arise from dysregulated tolerance mechanisms. This suggests that the limited polyreactivity observed for the bNt MAbs, and for HIV-1-Nt Abs in general, may arise through alternative mechanisms, such as extensive somatic mutation due to persistent antigen selection during chronic infection.

SUBMITTER: Singh H

PROVIDER: S-EPMC3334283 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Reactivity profiles of broadly neutralizing anti-HIV-1 antibodies are distinct from those of pathogenic autoantibodies.

Singh Harvir H Henry Kevin A KA Wu Sampson S T SS Chruscinski Andrzej A Utz Paul J PJ Scott Jamie K JK

AIDS (London, England) 20110601 10

<h4>Objective</h4>Broadly neutralizing antibodies (bNt Abs) against HIV-1 are rarely produced during natural infection, and efforts to induce such Abs by vaccination have been unsuccessful. Thus, elucidating the nature and cellular origins of bNt Abs is a high priority for vaccine research. As the bNt monoclonal Abs (MAbs) 2F5, 4E10 and 2G12 have been reported to bind select autoantigens, we investigated whether these MAbs display a broader range of autoreactivity and how their autoreactivity co ...[more]

PMID: 21508803

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Project description:Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Broadly neutralizing human antibodies (bNAbs) with exceptional activity against HIV-1 are currently being tested in HIV-1 prevention trials. The selection of anti-HIV-1 bNAbs for clinical development was primarily guided by their in vitro neutralizing activity against HIV-1 Env pseudotyped viruses. Here we report on the neutralizing activity of 9 anti-HIV-1 bNAbs now in clinical development against 126 Clade A, C, D PBMC-derived primary African isolates. The neutralizing potency and breadth of the bNAbs tested was significantly reduced compared to pseudotyped viruses panels. The difference in sensitivity between pseudotyped viruses and primary isolates varied from 3- to nearly 100-fold depending on the bNAb and the HIV-1 clade. Thus, the neutralizing activity of bNAbs against primary African isolates differs from their activity against pseudovirus panels. The data have significant implications for interpreting the results of ongoing HIV-1 prevention trials.IMPORTANCE HIV remains a major public health problem worldwide, and new therapies and preventive strategies are necessary for controlling the epidemic. Broadly neutralizing antibodies (bNAbs) have been developed in the past decade to fill this gap. The neutralizing activity of these antibodies against diverse HIV strains has mostly been measured using Env-pseudotyped viruses, which overestimate bNAb coverage and potency. In this study we measured the neutralizing activity of nine bNAbs against clade A, C, and D HIV isolates derived from cells of African patients living with HIV and produced in peripheral blood mononuclear cells. We found that the coverage and potency of bNAbs were often significantly lower than what was predicted by Env-psuedotyped viruses, and that this decrease was related to the bNAb biding site class. This data is important for the planning and analysis of clinical trials that seek to evaluate bNAbs for the treatment and prevention of HIV infection in Africa.

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Reactivity profiles of broadly neutralizing anti-HIV-1 antibodies are distinct from those of pathogenic autoantibodies.

Publications

Reactivity profiles of broadly neutralizing anti-HIV-1 antibodies are distinct from those of pathogenic autoantibodies.

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