HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
Nature (Impact Factor: 41.46). 10/2012; 492(7427). DOI: 10.1038/nature11604


Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection1, 2. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time3, 4. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design5, 6, 7, 8, 9. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy10, 11, 12, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.

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    • "Moreover, in this study three different bioanalytical approaches for glycoprofiling of human sera are described, including traditional ELISA-like method enzyme-linked lectin assay (ELLA), novel multiplexed lectin microarray format of analysis and ultrasensitive EISbased biosensing with immobilized lectins. Since glycosylation is the most common posttranslational modification of proteins (!50% of all eukaryotic proteins and !70% of all therapeutic proteins) [19] [32] a huge scientific effort is devoted to better understanding of their role in cell processes or to apply such knowledge to design better therapeutics or diagnostic tools [33] [34] [35] [36] [37] [38] [39] [40]. Thus, glycoprofiling of samples from SSc patients can be an alternative way for future early stage diagnostics of the SSc disease and other diseases including various types of cancer associated with aberrant glycosylation. "
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    ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease seriously affecting patient́s quality of life. The heterogeneity of the disease also means that identification and subsequent validation of biomarkers of the disease is quite challenging. A fully validated single biomarker for diagnosis, prognosis, disease activity and assessment of response to therapy is not yet available. The main aim of this study was to apply an alternative assay protocol to the immunoassay-based analysis of this disease by employment of sialic acid recognizing lectin Sambucus nigra agglutinin (SNA) to glycoprofile serum samples. To our best knowledge this is the first study describing direct lectin-based glycoprofiling of serum SSc samples. Three different analytical methods for glycoprofiling of serum samples relying on application of lectins are compared here from a bioanalytical point of view including traditional ELISA-like lectin-based method (ELLA), novel fluorescent lectin microarrays and ultrasensitive impedimetric lectin biosensors. Results obtained by all three bioanalytical methods consistently showed differences in the level of sialic acid present on glycoproteins, when serum from healthy people was compared to the one from patients having SSc. Thus, analysis of sialic acid content in human serum could be of a diagnostic value for future detection of SSc, but further work is needed to enhance selectivity of assays for example by glycoprofiling of a fraction of human serum enriched in antibodies for individual diagnostics.
    Full-text · Article · Jan 2015 · Analytica Chimica Acta
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    • "Passive antibody transfer studies might suffer from similar issues. For example, passively transferred neutralizing antibodies may have a short half-life in vivo and thus a short window of potential activity [11,12]. Therefore, we developed a protocol to challenge animals intrarectally with a low-dose of SIV multiple times in a short duration, an approach termed “rapid, repeated, low-dose” infection (RRLD). "
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    ABSTRACT: Background Simian immunodeficiency virus (SIV) infection of nonhuman primates is the predominant model for preclinical evaluation of human immunodeficiency virus (HIV) vaccines. These studies frequently utilize high-doses of SIV that ensure infection after a single challenge but do not recapitulate critical facets of sexual HIV transmission. Investigators are increasingly using low-dose challenges in which animals are challenged once every week or every two weeks in order to better replicate sexual HIV transmission. Using this protocol, some animals require over ten challenges before SIV infection is detectable, potentially inducing localized immunity. Moreover, the lack of certainty over which challenge will lead to productive infection prevents tissue sampling immediately surrounding the time of infection.FindingsHere we challenged Mauritian cynomolgus macaques with 100 50% tissue culture infectious doses (TCID50) of SIVmac239 intrarectally three times a day for three consecutive days. Ten of twelve animals had positive plasma viral loads after this challenge regimen.Conclusions This approach represents a straightforward advance in SIV challenge protocols that may avoid induction of local immunity, avoid inconsistent timing between last immunization and infection, and allow sampling immediately after infection using low-dose challenge protocols.
    Full-text · Article · Aug 2014 · Retrovirology
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    • "Humoral immunotherapy (e.g. neutralizing antibodies) is one possible approach to treating HIV [32–35]. As previously discussed, HIV-1 Env glycoprotein protects the virus from recognition by immune antibodies. "
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    ABSTRACT: More than 60 million people in the world have been diagnosed with human immunodeficiency virus (HIV) infections since the virus was recognized as the causative agent of acquired immunodeficiency syndrome (AIDS) in the 1980s. Even though more than half of the infected patients have died, effective disease treatment and prevention measures have not been established. Antiretroviral therapy is the only proven HIV treatment which sustains suppression of patient viremia. Current routine approaches to treat HIV infections are targeted at developing vaccines that will induce humoral or cell memory immune responses. However, developing an effective vaccine has been challenging because the HIV mutates rapidly, which allows the virus to evade immune surveillances established against the previous strain. In addition, the virus is able to quickly establish a reservoir and treatment is difficult because of the general lack of knowledge about HIV immune response mechanisms. This review introduces common disease symptoms and the progression of HIV infection with a brief summary of the current treatment approaches. Different cellular immune responses against HIV are also discussed, with emphasis on a nanotechnology research that has focused on probing T cell response to HIV infection. Furthermore, we discuss recent noteworthy nanotechnology updates on T cell response screening that are focused on HIV infection. Finally, we review potential future treatment strategies based on the correlations between T cell response and HIV infection.
    Full-text · Article · Jul 2014 · Bioscience Reports
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