Ancestral and consensus envelope immunogens for HIV-1 subtype C

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Virology (Impact Factor: 3.28). 10/2006; 352(2):438-49. DOI: 10.1016/j.virol.2006.05.011
Source: PubMed

ABSTRACT Immunogens based on "centralized" (ancestral or consensus) HIV-1 sequences minimize the genetic distance between vaccine strains and contemporary viruses and should thus elicit immune responses that recognize a broader spectrum of viral variants. However, the biologic, antigenic and immunogenic properties of such inferred gene products have to be validated experimentally. Here, we report the construction and characterization of the first full-length ancestral (AncC) and consensus (ConC) env genes of HIV-1 (group M) subtype C. The codon-usage-optimized genes expressed high levels of envelope glycoproteins that were incorporated into HIV-1 virions, mediated infection via the CCR5 co-receptor and retained neutralizing epitopes as recognized by plasma from patients with chronic HIV-1 subtype C infection. Guinea pigs immunized with AncC and ConC env DNA developed high titer binding, but no appreciable homologous or heterologous neutralizing antibodies. When tested by immunoblot analysis, sera from AncC and ConC env immunized guinea pigs recognized a greater number of primary subtype C envelope glycoproteins than sera from guinea pigs immunized with a contemporary subtype C env control. Mice immunized with AncC and ConC env DNA developed gamma interferon T cell responses that recognized overlapping peptides from the cognate ConC and a heterologous subtype C Env control. Thus, both AncC and ConC env genes expressed functional envelope glycoproteins that were immunogenic in laboratory animals and elicited humoral and cellular immune responses of comparable breadth and magnitude. These results establish the utility of centralized HIV-1 subtype C Env immunogens and warrant their continued evaluation as potential components of future AIDS vaccines.

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Available from: Feng Gao, Dec 01, 2014
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    • "In a review by Gao F et al. the use of centralized envelopes (consensus, center of the tree and ancestral) to induce HIV specific immune responses is covered (Gao 2007). The use of the centralized immunogens resulted in a superior breadth of cellular and humoral immune response (Kothe, Li et al. 2006; Liao, Sutherland et al. 2006; Kothe, Decker et al. 2007; Santra, Korber et al. 2008). In regard to generating mucosal immunity different vaccine strategies including vaccination at oral or vaginal in primates and use of adjuvants are being investigated to establish protective immune response at the mucosa (Peters, Peng et al. 2003; Duerr 2010; Sui, Zhu et al. 2010). "
    HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies, 10/2011; , ISBN: 978-953-307-665-2
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    • "Both recombinants were immunogenic, inducing IFN-γ-secreting cells in response to stimulation with both SF162 and TV1 Env peptides. To evaluate whether the Ad5hr-recombinants would elicit cellular immune responses against a broader range of HIV envelopes from subtype B and C isolates, consensus subtype B [31] and consensus subtype C [32] envelope peptides were also tested. Cross-reactive responses were elicited by both recombinants to the consensus B and C peptides (Fig. 2). "
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    ABSTRACT: An HIV Env immunogen capable of eliciting broad immunity is critical for a successful vaccine. We constructed and characterized adenovirus 5 host range mutant (Ad5hr) recombinants encoding HIV(SF162) gp160 (subtype B) and HIV(TV1) gp160 (subtype C). Immunization of mice with one or both induced cellular immunity to subtype B and C peptides by ELISpot, and antibody responses with high binding titers to HIV Env of subtypes A, B, C, and E. Notably, Ad5hr-HIV(TV1) gp160 induced better cellular immunity than Ad5hr-HIV(SF162) gp160, either alone or following co-administration. Thus, the TV1 Env recombinant alone may be sufficient for eliciting immune responses against both subtype B and C envelopes. Further studies of Ad5hr-HIV(TV1) gp160 in rhesus macaques will evaluate the suitability of this insert for a future phase I clinical trial using a replication-competent Ad4 vector.
    Vaccine 04/2010; 28(23):3963-71. DOI:10.1016/j.vaccine.2010.03.046 · 3.49 Impact Factor
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    • "The HIV-1 subtype B consensus full-length env gene sequence was codon-usage optimized as described (Haas et al., 1996;Andre et al., 1998;Gao et al., 2003;Kothe et al., 2006) and is available at Genbank under accession number DQ667594. All ConB env gene modifications were generated using the QuikChange Site-Directed Mutagenesis Kit (Invitrogen, Carlsbad, CA). "
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    ABSTRACT: "Centralized" (ancestral and consensus) HIV-1 envelope immunogens induce broadly cross-reactive T cell responses in laboratory animals; however, their potential to elicit cross-reactive neutralizing antibodies has not been fully explored. Here, we report the construction of a panel of consensus subtype B (ConB) envelopes and compare their biologic, antigenic, and immunogenic properties to those of two wild-type Env controls from individuals with early and acute HIV-1 infection. Glycoprotein expressed from full-length (gp160), uncleaved (gp160-UNC), truncated (gp145), and N-linked glycosylation site deleted (gp160-201N/S) versions of the ConB env gene were packaged into virions and, except for the fusion defective gp160-UNC, mediated infection via the CCR5 co-receptor. Pseudovirions containing ConB Envs were sensitive to neutralization by patient plasma and monoclonal antibodies, indicating the preservation of neutralizing epitopes found in contemporary subtype B viruses. When used as DNA vaccines in guinea pigs, ConB and wild-type env immunogens induced appreciable binding, but overall only low level neutralizing antibodies. However, all four ConB immunogens were significantly more potent than one wild-type vaccine at eliciting neutralizing antibodies against a panel of tier 1 and tier 2 viruses, and ConB gp145 and gp160 were significantly more potent than both wild-type vaccines at inducing neutralizing antibodies against tier 1 viruses. Thus, consensus subtype B env immunogens appear to be at least as good as, and in some instances better than, wild-type B env immunogens at inducing a neutralizing antibody response, and are amenable to further improvement by specific gene modifications.
    Virology 04/2007; 360(1):218-34. DOI:10.1016/j.virol.2006.10.017 · 3.28 Impact Factor
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