Abstract
It has been hypothesized that a single mutation at a highly conserved amino acid site (HCS) can be severely deleterious to HIV in most if not all isolate-specific genetic backgrounds. Consequently, potentially universal HIV-1 vaccines exclusively targeting highly conserved regions of the viral proteome have been proposed. To test this hypothesis, we examined the impact of 10 Gag-p24 and 9 Env-gp120 HCS single mutations on viral fitness. In the original founder sequence of the subject in whom these mutations were identified, all Gag-p24 HCS mutations significantly reduced viral replication fitness, including 7 that were lethal. Similar results were obtained at 9/10 sites when the same mutations were introduced into the founder sequences of two epidemiologically unlinked subjects. In contrast, none of the 9 Env-gp120 HCS mutations were lethal in the original founder sequence, and four had no fitness cost. Hence, HCS mutations in Gag-p24 are likely to be severely deleterious in different HIV-1 subtype B backgrounds; however, some HCS mutations in both Gag-p24 and Env-gp120 fragments can be well tolerated. Therefore, when designing HIV-1 immunogens that are intended to force the virus to nonviable escape pathways, the fitness constraints on the HIV segments included should be considered beyond their conservation level.
Highlights
VaxGen’s AIDSVAX vaccine, aimed at inducing neutralizing antibody responses [1,2,3], and Merck’s rAd5-based T-cell vaccine [4] both failed to provide protection against HIV acquisition or control after HIV infection
The underlying hypothesis of these approaches is that mutations at highly conserved amino acid sites (HCS) are likely to be detrimental to viral fitness and that the same HCS mutations will have a similar impact on different viral strains
Sixty-two percent (n = 197) of the Gag and 36% (n = 175) of the Env sites corresponded to HCS
Summary
VaxGen’s AIDSVAX vaccine, aimed at inducing neutralizing antibody responses [1,2,3], and Merck’s rAd5-based T-cell vaccine [4] both failed to provide protection against HIV acquisition or control after HIV infection. The RV144 trial of vaccination with a combination of ALVAC and AIDSVAX showed a modest reduction in HIV-1 acquisition in Thailand [7], new vaccine approaches are clearly needed, especially those that target features of the virus that will elicit more potent protective immunity. We and others [8,9,10] have proposed designing universal HIV-1 vaccine immunogens that would target highly conserved regions of the viral proteome in which mutations are predicted to compromise virus viability, and some would omit viral sequences that may be preferentially recognized but afford little or no containment of the virus [8]. The underlying hypothesis of these approaches is that mutations at highly conserved amino acid sites (HCS) are likely to be detrimental to viral fitness and that the same HCS mutations will have a similar impact on different viral strains
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
