Preclinical Studies of Human Immunodeficiency Virus/AIDS Vaccines: Inverse Correlation between Avidity of Anti-Env Antibodies and Peak Postchallenge Viremia

Zhao, Jun; Lai, Lilin; Amara, Rama Rao; Montefiori, David C.; Villinger, François; Chennareddi, Lakshmi; Wyatt, Linda S.; Moss, Bernard; Robinson, Harriet L.

doi:10.1128/jvi.02173-08

Cited by 59 publications

(59 citation statements)

References 41 publications

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“…Antibody affinity is a major characteristic of antibody-based vaccines (47,70,71), and due to the polyclonal nature of our samples, we assessed the apparent affinity of purified rabbit IgG samples to trimeric SF162 protein in the four highest responders of each vaccine group after the second, third, and fourth coimmunizations (weeks 6, 14, and 22, respectively) using biolayer interferometry. We measured each sample individually to determine overall kinetic binding characteristics, association constant (K on ), dissociation constant (K dis ), and K D (see Table S1 in the supplemental material).…”

Section: Fig 2 Longitudinal Heterologous Neutralizing Antibodies In Smentioning

confidence: 99%

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

Malherbe

Pissani

Sather

et al. 2014

J Virol

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Identifying characteristics of the human immunodeficiency virus type 1 (HIV-1) envelope that are effective in generating broad, protective antibodies remains a hurdle to HIV vaccine design. Emerging evidence of the development of broad and potent neutralizing antibodies in HIV-infected subjects suggests that founder and subsequent progeny viruses may express unique antigenic motifs that contribute to this developmental pathway. We hypothesize that over the course of natural infection, B cells are programmed to develop broad antibodies by exposure to select populations of emerging envelope quasispecies variants. To test this hypothesis, we identified two unrelated subjects whose antibodies demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in both subjects. We compared the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects. Rabbits were coimmunized four times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. The affinity of the polyclonal response increased as a function of boosting. The most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. These data have implications for vaccine development in describing a target time point to identify optimal envelope immunogens. IMPORTANCEVaccine protection against viral infections correlates with the presence of neutralizing antibodies; thus, vaccine components capable of generating potent neutralization are likely to be critical constituents in an effective HIV vaccine. However, vaccines tested thus far have elicited only weak antibody responses and very modest, waning protection. We hypothesized that B cells develop broad antibodies by exposure to the evolving viral envelope population and tested this concept using multiple envelopes from two subjects who developed neutralization breadth within a few years of infection. We compared different combinations of envelopes from each subject to identify the most effective immunogens and regimens. In each subject, use of HIV envelopes circulating during the early development and maturation of breadth generated more-potent antibodies that were modestly cross neutralizing. These data suggest a new approach to identifying envelope immunogens that may be more effective in generating protective antibodies in humans.A human immunodeficiency virus type 1 (HIV-1) envelope (Env) component that effectively stimulates the humoral arm of the adaptive immune response will be a critical ...

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Section: Fig 2 Longitudinal Heterologous Neutralizing Antibodies In Smentioning

confidence: 99%

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

Malherbe

Pissani

Sather

et al. 2014

J Virol

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show abstract

“…The importance of antibody avidity has been shown in studies associating low antibody avidity with poor protective efficacy of an RSV vaccine (Delgado et al, 2009). In contrast, high-avidity neutralizing (Barnett et al, 2010) and non-neutralizing (Zhao et al, 2009;Xiao et al, 2010) HIV-1 Env-specific antibodies have been inversely correlated with reduced SHIV viremia following challenge. Importantly, in the Xiao et al (2010) study, significant correlations were seen between antibody avidity and both functional antibody activities: ADCC and ADCVI, both also correlated with reduced viremia.…”

Section: Antibody Aviditymentioning

confidence: 99%

HIV Envelope-Specific Antibody and Vaccine Efficacy

Brocca-Cofano¹,

Xiao²,

Robert-Guroff³

2011

HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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“…Similarly, in the SHIV system, Robinson and colleagues have developed a DNA and MVA based vaccine which uses the large cloning capacity of the poxvirus vector to simultaneously encode gp41 and gag and thus produce virus-like particles. Highly avid antibodies to native gp41 appear to constitute a correlate of protection against peak viremia which transcends into improved control in the chronic phase of the infection (Zhao et al, 2009). Again, a similar strategy has not been tested with adenovirus vectors.…”

Section: Adenovirus Induced Antibody Responsesmentioning

confidence: 99%

Harnessing the Potential of Adenovirus Vectored Vaccines

Holst¹,

Thomsen²

2011

Viral Gene Therapy

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Preclinical Studies of Human Immunodeficiency Virus/AIDS Vaccines: Inverse Correlation between Avidity of Anti-Env Antibodies and Peak Postchallenge Viremia

Abstract: A major challenge for human immunodeficiency virus (HIV)/AIDS vaccines is the elicitation of anti-Env

Cited by 59 publications

References 41 publications

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

HIV Envelope-Specific Antibody and Vaccine Efficacy

Harnessing the Potential of Adenovirus Vectored Vaccines

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