Abstract
BackgroundThe development of an effective AIDS vaccine has been a formidable task, but remains a critical necessity. The well conserved membrane-proximal external region (MPER) of the HIV-1 gp41 glycoprotein is one of the crucial targets for AIDS vaccine development, as it has the necessary attribute of being able to elicit antibodies capable of neutralizing diverse isolates of HIV.Methodology/Principle FindingsGuided by X-ray crystallography, molecular modeling, combinatorial chemistry, and powerful selection techniques, we designed and produced six combinatorial libraries of chimeric human rhinoviruses (HRV) displaying the MPER epitopes corresponding to mAbs 2F5, 4E10, and/or Z13e1, connected to an immunogenic surface loop of HRV via linkers of varying lengths and sequences. Not all libraries led to viable chimeric viruses with the desired sequences, but the combinatorial approach allowed us to examine large numbers of MPER-displaying chimeras. Among the chimeras were five that elicited antibodies capable of significantly neutralizing HIV-1 pseudoviruses from at least three subtypes, in one case leading to neutralization of 10 pseudoviruses from all six subtypes tested.ConclusionsOptimization of these chimeras or closely related chimeras could conceivably lead to useful components of an effective AIDS vaccine. While the MPER of HIV may not be immunodominant in natural infection by HIV-1, its presence in a vaccine cocktail could provide critical breadth of protection.
Highlights
Despite the continued absence of an AIDS vaccine, it is widely agreed that a vaccine must be developed, as it is the most promising strategy for widespread protection against AIDS
While the membrane-proximal external region (MPER) of human immunodeficiency virus (HIV) may not be immunodominant in natural infection by HIV-1, its presence in a vaccine cocktail could provide critical breadth of protection
M medium [46] with 1-10% fetal bovine serum was used for propagation of the viruses; PA medium [46] with 1-10% fetal bovine serum was used for isolation and titering of the viruses; Dulbecco’s modified Eagle medium (DMEM; Gibco, BRL, Carlsbad, CA) was used for HeLa cell transfection; and AH medium [46] was used for large-scale propagations of the viruses
Summary
Despite the continued absence of an AIDS vaccine, it is widely agreed that a vaccine must be developed, as it is the most promising strategy for widespread protection against AIDS. The consensus has been that an ideal prophylactic AIDS vaccine will target the earliest events of infection by human immunodeficiency virus (HIV) and activate both the humoral and cellular immune responses [1,2,3] with an emphasis on eliciting broadly neutralizing antibodies, since B-cell responses are likely to confer the greatest long-term protection [4,5,6]. The greatest challenge to AIDS vaccine development has been the inability to isolate or engineer safe and broadly neutralizing immunogens that can block infection by the diverse circulating strains of HIV. The well conserved membrane-proximal external region (MPER) of the HIV-1 gp glycoprotein is one of the crucial targets for AIDS vaccine development, as it has the necessary attribute of being able to elicit antibodies capable of neutralizing diverse isolates of HIV
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