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Harnessing Natural Mosaics: Antibody-Instructed, Multi-Envelope HIV-1 Vaccine Design.

ABSTRACT: The year 2021 marks the 40th anniversary since physicians recognized symptoms of the acquired immunodeficiency syndrome (AIDS), a disease that has since caused more than 30 million deaths worldwide. Despite the passing of four decades, there remains no licensed vaccine for the human immunodeficiency virus type 1 (HIV-1), the etiologic agent of AIDS. Despite the development of outstanding anti-retroviral drugs, there are currently more than one-half million deaths each year due to AIDS. Here, we revisit a conventional vaccine strategy used for protection against variable pathogens like HIV-1, which combines an array of diverse surface antigens. The strategy uses antibody recognition patterns to categorize viruses and their surface antigens into groups. Then a leader is assigned for each group and group leaders are formulated into vaccine cocktails. The group leaders are 'natural mosaics', because they share one or more epitope(s) with each of the other group members. We encourage the application of this conventional approach to HIV-1 vaccine design. We suggest that the partnering of an antibody-instructed envelope cocktail with new vaccine vectors will yield a successful vaccine in the HIV-1 field.

SUBMITTER: Sealy RE

PROVIDER: S-EPMC8151930 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Harnessing Natural Mosaics: Antibody-Instructed, Multi-Envelope HIV-1 Vaccine Design.

Sealy Robert E RE Dayton Barry B Finkelstein David D Hurwitz Julia L JL

Viruses 20210511 5

The year 2021 marks the 40th anniversary since physicians recognized symptoms of the acquired immunodeficiency syndrome (AIDS), a disease that has since caused more than 30 million deaths worldwide. Despite the passing of four decades, there remains no licensed vaccine for the human immunodeficiency virus type 1 (HIV-1), the etiologic agent of AIDS. Despite the development of outstanding anti-retroviral drugs, there are currently more than one-half million deaths each year due to AIDS. Here, we ...[more]

PMID: 34064894

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Project description:Dominant antibody responses in vaccinees who received the HIV-1 multiclade (A, B, and C) envelope (Env) DNA/recombinant adenovirus virus type 5 (rAd5) vaccine studied in HIV-1 Vaccine Trials Network (HVTN) efficacy trial 505 (HVTN 505) targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs), which are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization. We found that the DNA/rAd5 vaccine elicited a higher frequency of gp41-reactive memory B cells than gp120-memory B cells in adult and neonatal RMs. Analysis of the vaccine-induced Env-reactive B cell repertoire revealed that the majority of HIV-1 Env-reactive antibodies in both adult and neonatal RMs were targeted to gp41. Interestingly, a subset of gp41-reactive antibodies isolated from RMs cross-reacted with host antigens, including autologous intestinal microbiota. Thus, gp41-containing DNA/rAd5 vaccine induced dominant gp41-microbiota cross-reactive antibodies derived from blood memory B cells in RMs as observed in the HVTN 505 vaccine efficacy trial. These data demonstrated that RMs can be used to investigate gp41 immunodominance in candidate HIV-1 vaccines. Moreover, colonization of neonatal RMs occurred within the first week of life, and immunization of neonatal RMs during this time also induced a dominant gp41-reactive antibody response.IMPORTANCE Our results are critical to current work in the HIV-1 vaccine field evaluating the phenomenon of gp41 immunodominance induced by HIV-1 Env gp140 in RMs and humans. Our data demonstrate that RMs are an appropriate animal model to study this phenomenon and to determine the immunogenicity in new HIV-1 Env trimer vaccine designs. The demonstration of gp41 immunodominance in memory B cells of both adult and neonatal RMs indicated that early vaccination could not overcome gp41 dominant responses.

Project description:IntroductionThe development of a human immunodeficiency virus 1 (HIV-1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly neutralizing antibodies (bNAbs), which likely involves the use of native-like HIV-1 envelope (Env) trimers at some or all stages of vaccination. Development of such trimers has been very difficult, but much progress has been made in the past decade, starting with the BG505 SOSIP trimer, elucidation of its atomic structure and implementing subsequent design iterations. This progress facilitated understanding the weaknesses of the Env trimer, fuelled structure-guided HIV-1 vaccine design and assisted in the development of new vaccine designs. This review summarizes the relevant literature focusing on studies using structural biology to reveal and define HIV-1 Env sites of vulnerability; to improve Env trimers, by creating more stable versions; understanding antibody responses in preclinical vaccination studies at the atomic level; understanding the glycan shield; and to improve "on-target" antibody responses versus "off-target" responses.MethodsThe authors conducted a narrative review of recently published articles that made a major contribution to HIV-1 structural biology and vaccine design efforts between the years 2000 and 2021.DiscussionThe field of structural biology is evolving at an unprecedented pace, where cryo-electron microscopy (cryo-EM) and X-ray crystallography provide complementary information. Resolving protein structures is necessary for defining which Env surfaces are accessible for the immune system and can be targeted by neutralizing antibodies. Recently developed techniques, such as electron microscopy-based polyclonal epitope mapping (EMPEM) are revolutionizing the way we are analysing immune responses and shed light on the immunodominant targets on new vaccine immunogens. Such information accelerates iterative vaccine design; for example, by reducing undesirable off-target responses, while improving immunogens to drive the more desirable on-target responses.ConclusionsResolving high-resolution structures of the HIV-1 Env trimer was instrumental in understanding and improving recombinant HIV-1 Env trimers that mimic the structure of viral HIV-1 Env spikes. Newly emerging techniques in structural biology are aiding vaccine design efforts and improving immunogens. The role of structural biology in HIV-1 vaccine design has indeed become very prominent and is unlikely to diminish any time soon.

Dataset Information

Harnessing Natural Mosaics: Antibody-Instructed, Multi-Envelope HIV-1 Vaccine Design.

Publications

Harnessing Natural Mosaics: Antibody-Instructed, Multi-Envelope HIV-1 Vaccine Design.

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