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Why HIV virions have low numbers of envelope spikes: implications for vaccine development.

Schiller J, Chackerian B - PLoS Pathog. (2014)

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

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Why has HIV evolved this exceptional virion structure? We believe that studies of human papillomavirus (HPV) virus-like particles (VLPs), which are the basis of the highly successful HPV vaccine, may provide the conceptual underpinning for answering this question and key insights for developing effective HIV prophylactic vaccines... However, by evolving an escape mechanism that relies on ignorance of the virions by the humoral immune system, HPVs have not evolved strategies to evade induction of potent neutralizing antibody responses if the virions are exposed to the systemic immune system, as is readily accomplished by standard parenteral injection... Thus, it is not surprising, at least in retrospect, that intramuscular injection of HPV L1 VLPs (which mimic the outer surface of the authentic virion) induces a virion antibody response that is highly protective against HPV infection and associated neoplasia... Remarkably, recognition of this epitope pattern is dominant over the mechanisms that normally promote B cell tolerance to self... For example, we found that display of tumor necrosis factor alpha (TNFα), a normally tolerogenic self-antigen, in a high-density array on an HPV VLP leads to long-lasting IgG responses against TNFα that are essentially equivalent to those against the foreign epitopes on the VLP... In contrast to HPV VLP vaccination, it is well documented that neutralizing antibodies are exceptionally slow to develop during HIV infection, and nearly all broadly neutralizing antibodies invariably have undergone a large number of hypersomatic mutations... The low density of virion epitopes also raises the potential for HIV to evolve critical envelope determinates that are partially cross-reactive with self, so that mechanisms of self-tolerance can hinder induction of antibodies to them... Since HIV env epitopes may be more self cross-reactive than the capsid proteins of most viruses, it will be critical to carefully evaluate the possibility that pathogenic autoantibodies are generated by the vaccines... For example, in contrast to HPV VLPs, the hepatitis B surface antigen particles that are the basis of all current hepatitis B virus (HBV) vaccines generate detectable antibodies in only a minority of subjects after one dose and titers do not routinely stabilize, even after three doses... To inform design of prophylactic vaccines for HIV, it seems worthwhile to determine the key differences that account for the variability in the intrinsic immunogenicity of various VLP platforms and to evaluate their ability to break B cell tolerance to displayed self-antigens... In summary, we postulate that HIV has evolved an exceptionally low number of envelope spikes so that effective neutralizing antibodies can't be generated through self-reactive intermediates and therefore may not have evolved effective defenses against vaccines that can... In trading low efficiency of transmission for delayed induction of an effective neutralizing antibody response, the virus may have created an Achilles heel that might be exploited by a vaccine that relies on high-density virus-like display.

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What's different about HIV virions?Surface projections of bovine papillomavirus (BPV), HIV, dengue virus, and influenza virus are shown (not to scale). The images of papillomavirus (PV) and dengue virus were obtained from the Viper database (PMID: 18981051). The image of influenza virus is courtesy of cdc.gov. The HIV image was generously provided by Sriram Subramaniam, National Cancer Institute.
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ppat-1004254-g001: What's different about HIV virions?Surface projections of bovine papillomavirus (BPV), HIV, dengue virus, and influenza virus are shown (not to scale). The images of papillomavirus (PV) and dengue virus were obtained from the Viper database (PMID: 18981051). The image of influenza virus is courtesy of cdc.gov. The HIV image was generously provided by Sriram Subramaniam, National Cancer Institute.

Mentions: The major structural proteins of most viruses, including both naked icosahedral and enveloped types, are present in a dense array on the virion surface. This pattern has likely evolved to promote structural integrity, maximize cell binding and entry, and minimize genome size. HIV and related simian lentiviruses are unusual in having a low density of envelope protein spikes on their surfaces (Figure 1) [1]. Why has HIV evolved this exceptional virion structure? We believe that studies of human papillomavirus (HPV) virus-like particles (VLPs), which are the basis of the highly successful HPV vaccine, may provide the conceptual underpinning for answering this question and key insights for developing effective HIV prophylactic vaccines.


Why HIV virions have low numbers of envelope spikes: implications for vaccine development.

Schiller J, Chackerian B - PLoS Pathog. (2014)

What's different about HIV virions?Surface projections of bovine papillomavirus (BPV), HIV, dengue virus, and influenza virus are shown (not to scale). The images of papillomavirus (PV) and dengue virus were obtained from the Viper database (PMID: 18981051). The image of influenza virus is courtesy of cdc.gov. The HIV image was generously provided by Sriram Subramaniam, National Cancer Institute.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4125284&req=5

ppat-1004254-g001: What's different about HIV virions?Surface projections of bovine papillomavirus (BPV), HIV, dengue virus, and influenza virus are shown (not to scale). The images of papillomavirus (PV) and dengue virus were obtained from the Viper database (PMID: 18981051). The image of influenza virus is courtesy of cdc.gov. The HIV image was generously provided by Sriram Subramaniam, National Cancer Institute.
Mentions: The major structural proteins of most viruses, including both naked icosahedral and enveloped types, are present in a dense array on the virion surface. This pattern has likely evolved to promote structural integrity, maximize cell binding and entry, and minimize genome size. HIV and related simian lentiviruses are unusual in having a low density of envelope protein spikes on their surfaces (Figure 1) [1]. Why has HIV evolved this exceptional virion structure? We believe that studies of human papillomavirus (HPV) virus-like particles (VLPs), which are the basis of the highly successful HPV vaccine, may provide the conceptual underpinning for answering this question and key insights for developing effective HIV prophylactic vaccines.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Why has HIV evolved this exceptional virion structure? We believe that studies of human papillomavirus (HPV) virus-like particles (VLPs), which are the basis of the highly successful HPV vaccine, may provide the conceptual underpinning for answering this question and key insights for developing effective HIV prophylactic vaccines... However, by evolving an escape mechanism that relies on ignorance of the virions by the humoral immune system, HPVs have not evolved strategies to evade induction of potent neutralizing antibody responses if the virions are exposed to the systemic immune system, as is readily accomplished by standard parenteral injection... Thus, it is not surprising, at least in retrospect, that intramuscular injection of HPV L1 VLPs (which mimic the outer surface of the authentic virion) induces a virion antibody response that is highly protective against HPV infection and associated neoplasia... Remarkably, recognition of this epitope pattern is dominant over the mechanisms that normally promote B cell tolerance to self... For example, we found that display of tumor necrosis factor alpha (TNFα), a normally tolerogenic self-antigen, in a high-density array on an HPV VLP leads to long-lasting IgG responses against TNFα that are essentially equivalent to those against the foreign epitopes on the VLP... In contrast to HPV VLP vaccination, it is well documented that neutralizing antibodies are exceptionally slow to develop during HIV infection, and nearly all broadly neutralizing antibodies invariably have undergone a large number of hypersomatic mutations... The low density of virion epitopes also raises the potential for HIV to evolve critical envelope determinates that are partially cross-reactive with self, so that mechanisms of self-tolerance can hinder induction of antibodies to them... Since HIV env epitopes may be more self cross-reactive than the capsid proteins of most viruses, it will be critical to carefully evaluate the possibility that pathogenic autoantibodies are generated by the vaccines... For example, in contrast to HPV VLPs, the hepatitis B surface antigen particles that are the basis of all current hepatitis B virus (HBV) vaccines generate detectable antibodies in only a minority of subjects after one dose and titers do not routinely stabilize, even after three doses... To inform design of prophylactic vaccines for HIV, it seems worthwhile to determine the key differences that account for the variability in the intrinsic immunogenicity of various VLP platforms and to evaluate their ability to break B cell tolerance to displayed self-antigens... In summary, we postulate that HIV has evolved an exceptionally low number of envelope spikes so that effective neutralizing antibodies can't be generated through self-reactive intermediates and therefore may not have evolved effective defenses against vaccines that can... In trading low efficiency of transmission for delayed induction of an effective neutralizing antibody response, the virus may have created an Achilles heel that might be exploited by a vaccine that relies on high-density virus-like display.

Show MeSH
Related in: MedlinePlus