Abstract
The ability of human immunodeficiency virus type 1 (HIV-1) to develop high levels of genetic diversity, and thereby acquire mutations to escape immune pressures, contributes to the difficulties in producing a vaccine. Possibly no single HIV-1 sequence can induce sufficiently broad immunity to protect against a wide variety of infectious strains, or block mutational escape pathways available to the virus after infection. The authors describe the generation of HIV-1 immunogens that minimizes the phylogenetic distance of viral strains throughout the known viral population (the center of tree [COT]) and then extend the COT immunogen by addition of a composite sequence that includes high-frequency variable sites preserved in their native contexts. The resulting COT+ antigens compress the variation found in many independent HIV-1 isolates into lengths suitable for vaccine immunogens. It is possible to capture 62% of the variation found in the Nef protein and 82% of the variation in the Gag protein into immunogens of three gene lengths. The authors put forward immunogen designs that maximize representation of the diverse antigenic features present in a spectrum of HIV-1 strains. These immunogens should elicit immune responses against high-frequency viral strains as well as against most mutant forms of the virus.
Highlights
The failure of AIDS vaccine efforts in the past 20-plus years is thought to be due, in part, to the enormous viral antigenic diversity found within and among patients with human immunodeficiency virus type 1 (HIV-1) infection
Focusing on the use of whole viral protein sequences, natural strains (NSs) as well as consensus (CON) sequences are being used as a means to minimize the abrogating effect of antigenic diversity in vaccine antigens [2,6,7], as are the inferred most recent common ancestors (MRCA, or ANC) [6,8,9,10] of targeted virus populations defined as sequences that reside at the basal node of the set of in-group sequences in a phylogenetic tree reconstruction [11]
In an effort to develop antigens that capture both the summary of circulating variation found in CON estimates, and the coupling of mutations generated with inferred ANC sequences, we have developed an alternative computational method that reconstructs the ancestral state sequence at the center of tree (COT)
Summary
The failure of AIDS vaccine efforts in the past 20-plus years is thought to be due, in part, to the enormous viral antigenic diversity found within and among patients with human immunodeficiency virus type 1 (HIV-1) infection. New methods of combining epitopes are being explored in vaccine design, including production of pseudoprotein strings of T cell epitopes [4], and the synthetic scrambled antigen vaccine (SAVINE) [5], which employs consensus overlapping peptide sets from HIV-1 proteins scrambled together. Focusing on the use of whole viral protein sequences, natural strains (NSs) as well as consensus (CON) sequences are being used as a means to minimize the abrogating effect of antigenic diversity in vaccine antigens [2,6,7], as are the inferred most recent common ancestors (MRCA, or ANC) [6,8,9,10] of targeted virus populations defined as sequences that reside at the basal node of the set of in-group sequences in a phylogenetic tree reconstruction [11]. HIV-1 env sequences representing both the CON and ANC have been prepared and studied, but neither has generated exceptionally broad humoral immune reactivity in initial small animal studies [7,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
