Diversity Considerations in HIV-1 Vaccine Selection

Gaschen, Brian; Taylor, Jamie; Yusim, Karina; Foley, Brian; Gao, Feng; Lang, Dorothy; Novitsky, Vladimir; Haynes, Barton F.; Hahn, Beatrice H.; Bhattacharya, Tanmoy; Korber, Bette T.

doi:10.1126/science.1070441

Cited by 715 publications

(615 citation statements)

References 39 publications

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“…For example, a clade-1 whole-virus vaccine raised a significant neutralizing antibody response against the homologous strain, but much less so against heterologous strains (10). One way to minimize the sequence diversity between a vaccine strain and circulating viruses is to create an artificial sequence to ''centralize'' the immunogenicity of the vaccine antigen (18,26,27). One approach is to construct, computationally, a consensus sequence that resides toward the middle of the viral phylogenetic tree.…”

Section: Discussionmentioning

confidence: 99%

A consensus–hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses

Chen

Cheng²,

Huang³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

135

123

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H5N1 influenza viruses have spread extensively among wild birds and domestic poultry. Cross-species transmission of these viruses to humans has been documented in over 380 cases, with a mortality rate of Ϸ60%. There is great concern that a H5N1 virus would acquire the ability to spread efficiently between humans, thereby becoming a pandemic threat. An H5N1 influenza vaccine must, therefore, be an integral part of any pandemic preparedness plan. However, traditional methods of making influenza vaccines have yet to produce a candidate that could induce potently neutralizing antibodies against divergent strains of H5N1 influenza viruses. To address this need, we generated a consensus H5N1 hemagglutinin (HA) sequence based on data available in early 2006. This sequence was then optimized for protein expression before being inserted into a DNA plasmid (pCHA5). Immunizing mice with pCHA5, delivered intramuscularly via electroporation, elicited antibodies that neutralized a panel of virions that have been pseudotyped with the HA from various H5N1 viruses (clades 1, 2.1, 2.2, 2.3.2, and 2.3.4). Moreover, immunization with pCHA5 in mice conferred complete (clades 1 and 2.2) or significant (clade 2.1) protection from H5N1 virus challenges. We conclude that this vaccine, based on a consensus HA, could induce broad protection against divergent H5N1 influenza viruses and thus warrants further study.

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Section: Discussionmentioning

confidence: 99%

A consensus–hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses

Chen

Cheng²,

Huang³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

135

123

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“…Although an estimated 5.5 million people are living with HIV in South Africa7 where HIV-1 subtype C prevails,14,15 the majority of studies on HIV have been done on HIV-1 subtype B, which is responsible for infections in North America, Europe and Australia 15,16. Subtype C accounts for 55 to 60% of all HIV infections worldwide and differs as much as 30% in its genome from subtype B 17,18.…”

Section: Introductionmentioning

confidence: 99%

Is HIV-1 infection associated with endothelial dysfunction in a population of African ancestry in South Africa?

Fourie¹,

Rooyen²,

Pieters³

et al. 2011

CardioVascular Journal of Africa

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The chronic infection status suffered by HIV-infected individuals promotes chronic arterial inflammation and injury, which leads to dysfunction of the endothelium, atherosclerosis and thrombosis. Although HIV-1 subtype C is prevalent in South Africa and accounts for almost a third of the infections worldwide, this subtype differs genetically from HIV-1 subtype B on which the majority of studies have been done. The objective of this study was to assess whether newly identified, never-treated, HIV-1-infected South African participants showed signs of endothelial dysfunction, accelerated atherosclerosis and increased blood coagulation.We compared 300 newly diagnosed (never antiretroviral-treated) HIV-infected participants to 300 age-, gender-, body mass index- and locality-matched uninfected controls. Levels of high-density lipoprotein cholesterol (HDL-C), triglycerides, interleukin-6 (IL-6), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), fibrinogen and plasminogen activator inhibitor-1 (PAI-1), and carotid radialis pulse wave velocity (cr-PWV) were determined. The HIV-infected participants showed lower HDL-C and higher IL-6, CRP, ICAM-1 and VCAM-1 levels compared to the uninfected controls. No differences in fibrinogen and PAI-1 levels were detected. A continuous positive trend of increasing age with cr-PWV was detected in the HIV-infected group.Our findings suggest inflammatory injury of the endothelium, pointing to endothelial dysfunction of never-treated HIV-1-infected South Africans of African ancestry. Although no indication of a prothrombotic state could be detected, there was an indication of accelerated vascular aging and probable early atherosclerosis in the older HIV-infected participants.

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“…ancestral immunogen ͉ equine infectious anemia virus ͉ lentivirus G enomic and antigenic variation are recognized by the global scientific community as fundamental characteristics of HIV type 1 (HIV-1) infection, and it is widely accepted, although unproven, that HIV-1 antigenic diversity presents a major obstacle to HIV-1/AIDS vaccine development (1)(2)(3)(4)(5). Lentiviral antigenic variation is most pronounced in the viral Env proteins that serve as initial primary targets for host immune responses.…”

mentioning

confidence: 99%

Envelope variation as a primary determinant of lentiviral vaccine efficacy

Craigo

Zhang

Barnes

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Lentiviral envelope antigenic variation and associated immune evasion are believed to present major obstacles to effective vaccine development. Although this perception is widely assumed by the scientific community, there is, to date, no rigorous experimental data assessing the effect of increasing levels of lentiviral Env variation on vaccine efficacy. It is our working hypothesis that Env is, in fact, a primary determinant of vaccine effectiveness. We previously reported that a successful experimental attenuated equine infectious anemia virus vaccine, derived by mutation of the viral S2 accessory gene, provided 100% protection from disease after virulent virus challenge. Here, we sought to comprehensively test our hypothesis by challenging vaccinated animals with proviral strains of defined, increasing Env variation, using variant envelope SU genes that arose naturally during experimental infection of ponies with equine infectious anemia virus. The reference attenuated vaccine combined with these variant Env challenge strains facilitated evaluation of the protection conferred by ancestral immunogens, because the Env of the attenuated vaccine is a direct ancestor to the variant proviral strain Envs. The results demonstrated that ancestral Env proteins did not impart broad levels of protection against challenge. Furthermore, the results displayed a significant inverse linear correlation of Env divergence and protection from disease. This study demonstrates potential obstacles to the use of single isolate ancestral Env immunogens. Finally, these findings reveal that relatively minor Env variation can pose a substantial challenge to lentiviral vaccine immunity, even when attenuated vaccines are used that, to date, achieve the highest levels of vaccine protection.ancestral immunogen ͉ equine infectious anemia virus ͉ lentivirus

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Diversity Considerations in HIV-1 Vaccine Selection

Cited by 715 publications

References 39 publications

A consensus–hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses

A consensus–hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses

Is HIV-1 infection associated with endothelial dysfunction in a population of African ancestry in South Africa?

Envelope variation as a primary determinant of lentiviral vaccine efficacy

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