Progress on the induction of neutralizing antibodies against HIV type 1 (HIV-1).
ABSTRACT Infection with HIV type 1 (HIV-1), the causative agent of AIDS, is one of the most catastrophic pandemics to affect human healthcare in the latter 20th century. The best hope of controlling this pandemic is the development of a successful prophylactic vaccine. However, to date, this goal has proven to be exceptionally elusive. The recent failure of an experimental vaccine in a phase IIb study, named the STEP trial, intended solely to elicit cell-mediated immune responses against HIV-1, has highlighted the need for a balanced immune response consisting of not only cellular immunity but also a broad and potent humoral antibody response that can prevent infection with HIV-1. This article reviews the efforts made up to this point to elicit such antibody responses, especially with regard to the use of a DNA prime-protein boost regimen, which has been proven to be a highly effective platform for the induction of neutralizing antibodies in both animal and early-phase human studies.
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ABSTRACT: HIV-1 infection results in the development of a diverging quasispecies unique to each infected individual. Envelope (Env)-specific neutralizing antibodies (NAbs) typically develop over months to years after infection and initially are limited to the infecting virus. In some subjects, antibody responses develop that neutralize heterologous isolates (HNAbs), a phenomenon termed broadening of the NAb response. Studies of co-crystalized antibodies and proteins have facilitated the identification of some targets of broadly neutralizing monoclonal antibodies (NmAbs) capable of neutralizing many or most heterologous viruses; however, the ontogeny of these antibodies in vivo remains elusive. We hypothesize that Env protein escape variants stimulate broad NAb development in vivo and could generate such NAbs when used as immunogens. Here we test this hypothesis in rabbits using HIV Env vaccines featuring: (1) use of individual quasispecies env variants derived from an HIV-1 subtype A-infected subject exhibiting high levels of NAbs within the first year of infection that increased and broadened with time; (2) motif optimization of envs to enhance in vivo expression of DNA formulated as vaccines; and (3) a combined DNA plus protein boosting regimen. Vaccines consisted of multiple env variants delivered sequentially and a simpler regimen that utilized only the least and most divergent clones. The simpler regimen was as effective as the more complex approach in generating modest HNAbs and was more efficient when modified, motif-optimized DNA was used in combination with trimeric gp140 protein. This is a rationally designed strategy that facilitates future vaccine design by addressing the difficult problem of generating HNAbs to HIV by empirically testing the immunogenicity of naturally occurring quasispecies env variants.Vaccine 06/2012; 30(37):5519-26. DOI:10.1016/j.vaccine.2012.06.042 · 3.49 Impact Factor
Chapter: Immunotherapies and VaccinesHIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies, 10/2011; , ISBN: 978-953-307-665-2
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ABSTRACT: Over the past decade, there has been an explosion of information related to the protein-protein interactions within specific organisms. However, our understanding of the interactions between a pathogen and its host has lagged behind. This research uses ordinary differential equations and interaction data to model the progression of H. pylori infection, a major risk factor for gastric cancer. This model allows the study of proteins in the MAP Kinase and Apoptosis pathways and their change under bacterial stimulation. Microarray experiments performed on epithelial cells confirmed the time-course of the infection progression. These techniques were incorporated into the study of the HIV-1 viral infection that has a larger number of interactions, a handful of major interactions in H. pylori versus hundreds in HIV-1 infection. Interaction information gathered from human sequence motifs co-opted by HIV-1 for infection formed the basis of a predictor for the progression of the infection. Since HIV-1 easily develops resistance to multiple anti-retrovirals and high viral loads lead to increased mortality and morbidity, it is important to pick a drug that will inhibit viral replication. A logistic regression model trained with these sequence motifs as predictors has a high accuracy and specificity in choosing the correct drug when predicting historical samples. In an effort to expand these historical samples, which sequence only a small fragment of the HIV-1 genome, a viral linkage map was developed. This linkage map, similar to the human HAPMAP project, describes the evolutionary linkage across the HIV-1 genome. This allows researchers to gather the likely mutations on unsequenced regions of the virus and is the first step in a whole viral genome view of HIV-1 infection.