Ancestral and consensus envelope immunogens for HIV-1 subtype C

Duke University, Durham, North Carolina, United States
Virology (Impact Factor: 3.32). 10/2006; 352(2):438-49. DOI: 10.1016/j.virol.2006.05.011
Source: PubMed


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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    • "These included five subtype A, seven subtype B and eight subtype C envelope pseudoviruses as depicted in Table 2. Tier 1, 2 and 3 viruses were stratified previously based on a continuum of patterns of neutralization sensitivity—with tier 1A being the most sensitive, tier 1B above average, tier 2 displaying moderate to low sensitivity and tier 3 displaying the lowest sensitivity to neutralization (Seaman et al., 2010). The ConC plasmid based on the consensus of all the HIV-1 subtype C sequences from the Los Alamos database by 2001 was obtained from Dr Feng Gao (Kothe et al., 2006). The envelope plasmids containing single point mutations are described by Gray et al. (2011). "
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    ABSTRACT: Neutralizing (nAbs) and high affinity binding antibodies may be critical for an efficacious HIV-1 vaccine. We characterized virus-specific nAbs and binding antibody responses over 21 months in eight HIV-1 subtype C chronically infected individuals with heterogeneous rates of disease progression. Autologous nAb titers of study exit plasma against study entry viruses were significantly higher than contemporaneous responses at study entry (p=0.002) and exit (p=0.01). NAb breadth and potencies against subtype C viruses were significantly higher than for subtype A (p=0.03 and p=0.01) or B viruses (p=0.03; p=0.05) respectively. Gp41-IgG binding affinity was higher than gp120-IgG (p=0.0002). IgG-FcγR1 affinity was significantly higher than FcγRIIIa (p<0.005) at study entry and FcγRIIb (p<0.05) or FcγRIIIa (p<0.005) at study exit. Evolving IgG binding suggests alteration of immune function mediated by binding antibodies. Evolution of nAbs was a potential marker of HIV-1 disease progression.
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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). "

    Full-text · Chapter · Oct 2011
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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.
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