Muons penetrate much further than X-rays, they do essentially zero damage, and they are provided for free by the cosmos.
Image credit: Science Source/Digital Globe.
Contributed by Arup K. Chakraborty, December 28, 2020 (sent for review November 2, 2020; reviewed by Julie McElrath and Martin Weigt)
Significance
HIV is a highly mutable pathogen that can mutate to evade vaccine-induced immune responses, thus negating the vaccine’s protective effects. If mutations that evade immune responses incur a fitness penalty for the virus, other mutations can evolve to partially compensate for fitness loss. Accounting for such effects, we designed a single long peptide immunogen comprised of parts of HIV proteins wherein mutations would be difficult to evolve without fitness penalties for the virus. This designed immunogen was expressed in adenovirus vectors, which are in clinical development (e.g., for COVID-19). Monkeys immunized with our vaccine exhibited strong T-cell responses directed toward regions contained in our immunogen. This suggests that further exploration of this vaccine for use in humans is warranted.
Abstract
An effective vaccine that can protect against HIV infection does not exist. A major reason why a vaccine is not available is the high mutability of the virus, which enables it to evolve mutations that can evade human immune responses. This challenge is exacerbated by the ability of the virus to evolve compensatory mutations that can partially restore the fitness cost of immune-evading mutations. Based on the fitness landscapes of HIV proteins that account for the effects of coupled mutations, we designed a single long peptide immunogen comprising parts of the HIV proteome wherein mutations are likely to be deleterious regardless of the sequence of the rest of the viral protein. This immunogen was then stably expressed in adenovirus vectors that are currently in clinical development. Macaques immunized with these vaccine constructs exhibited T-cell responses that were comparable in magnitude to animals immunized with adenovirus vectors with whole HIV protein inserts. Moreover, the T-cell responses in immunized macaques strongly targeted regions contained in our immunogen. These results suggest that further studies aimed toward using our vaccine construct for HIV prophylaxis and cure are warranted.
Footnotes
- ↵1To whom correspondence may be addressed. Email: dbarouch{at}bidmc.harvard.edu or arupc{at}mit.edu.
Author contributions: D.K.M., J.P.B., D.H.B., and A.K.C. designed research; D.K.M., J.P.B., L.P., A.C., and E.B. performed research; D.K.M., A.G., D.H.B., and A.K.C. analyzed data; and D.K.M., D.H.B., and A.K.C. wrote the paper.
Reviewers: J.M., Fred Hutchinson Cancer Research Center; and M.W., Sorbonne University.
Competing interest statement: The authors have filed an application for a patent on the immunogen.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2022496118/-/DCSupplemental.
Data Availability.
All study data are included in the article and/or SI Appendix.
Published under the PNAS license.
References
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Adenovirus-vectored vaccine containing multidimensionally conserved parts of the HIV proteome is immunogenic in rhesus macaques
Article Classifications
- Biological Sciences
- Immunology and Inflammation
- Physical Sciences
- Biophysics and Computational Biology
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