Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

Fischer, Will; Apetrei, Cristian; Santiago, Mario L.; Li, Yingying; Gautam, Rajeev; Pandrea, Ivona; Shaw, George M.; Hahn, Beatrice H.; Letvin, Norman L.; Nabel, Gary J.; Korber, Bette T.

doi:10.1128/jvi.01862-12

Cited by 30 publications

(43 citation statements)

References 92 publications

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“…In terms of vulnerability to neutralizing antibodies, most of the SIVsm Envs in the panel seemed to behave more similarly to HIV-1 than HIV-2 Envs. The driving force for masking of conserved epitopes during natural infection with SIVsm is not immediately clear, given evidence of lower diversifying selection in Env gp120 (101) and lower autologous neutralizing antibody titers in naturally infected sooty mangabeys (39) than individuals infected with HIV-1. Unfortunately, the determinants of neutralization pan-resistance in some of the tier 3 SIVsm Envs or the identification of reagents that neutralize them will require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Kilgore

Murphy

Burton

et al. 2015

J Virol

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Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector-and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen. IMPORTANCEMany in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodi...

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Section: Discussionmentioning

confidence: 99%

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Kilgore

Murphy

Burton

et al. 2015

J Virol

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“…Taken together, these studies demonstrated the potential of centralized and polyvalent vaccines to enhance the immune coverage of diverse HIV-1 strains by expanding the breadth and the depth of cellular immune responses. In contrast to HIV mosaics conferring protection in an SHIV challenge model, SIV mosaic Env designs based on a small set of available sooty mangabey natural SIV variants (30) did not show a protective effect against infection (9). The lack of protection from infection in the SIV case might have been due to basing the mosaic design on very limited sampling of a less appropriate population (for a detailed discussion, see Fischer et al (30).…”

mentioning

confidence: 99%

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

Hulot

Korber

Giorgi

et al. 2015

J Virol

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An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4 ؉ and CD8؉ T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-␥) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCEThere is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

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“…In total, we analyzed 10,353 HIV-1 and 17 SIV cpz sequences. Maximum likelihood analysis for group M subtype-specific and SIV cpz consensus sequences revealed relatively low evolutionary diversity for the ISS element with a mean genetic distance of 0.06 Ϯ 0.02 substitution per site in contrast to ϳ0.45 substitution per site (42) reported for the surrounding HIV-1 env region as a whole. Fig.…”

Section: The Iss Element Folds Into a Phylogenetically Conserved Stemmentioning

confidence: 77%

Solution Structure of the HIV-1 Intron Splicing Silencer and Its Interactions with the UP1 Domain of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1

Jain

Morgan

Rife

et al. 2016

Journal of Biological Chemistry

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Splicing patterns in human immunodeficiency virus type 1 (HIV-1) are maintained through cis regulatory elements that recruit antagonistic host RNA-binding proteins. The activity of the 3 acceptor site A7 is tightly regulated through a complex network of an intronic splicing silencer (ISS), a bipartite exonic splicing silencer (ESS3a/b), and an exonic splicing enhancer (ESE3). Because HIV-1 splicing depends on protein-RNA interactions, it is important to know the tertiary structures surrounding the splice sites. Herein, we present the NMR solution structure of the phylogenetically conserved ISS stem loop. ISS adopts a stable structure consisting of conserved UG wobble pairs, a folded 2X2 (GU/UA) internal loop, a UU bulge, and a flexible AGUGA apical loop. Calorimetric and biochemical titrations indicate that the UP1 domain of heterogeneous nuclear ribonucleoprotein A1 binds the ISS apical loop site-specifically and with nanomolar affinity. Collectively, this work provides additional insights into how HIV-1 uses a conserved RNA structure to commandeer a host RNA-binding protein.Human immunodeficiency virus type 1 (HIV-1) 2 requires controlled synthesis of its protein complement for persistent infection and successful virion production. Genome expression is tightly regulated at the levels of transcription, splicing, mRNA nuclear export, and translation (1). RNA polymerase II-dependent transcription yields a 9-kilobase (kb) polycistronic transcript that undergoes multiple rounds of alternative splicing to produce upward of 100 different viral mRNAs that are classified by their intron composition: unspliced, incompletely spliced (4 kb), and completely spliced (2 kb) (2, 3). During early phase HIV-1 replication, cytoplasmic levels of the 2-kb transcripts predominate to encode Tat, Rev, and Nef. Accumulation of unspliced and 4-kb transcripts coincides with the transition to late phase replication and expression of Gag, Gag/Pol, Vpr, Vif, and Env/Vpu. Thus, HIV-1 splicing pathways are essential components of the viral replication cycle and represent new targets for therapeutic intervention (3, 4).The identities of HIV-1 transcripts are determined by the combinatorial use of several 5Ј donor and 3Ј acceptor splice sites. Efforts to understand mechanisms of HIV-1 splicing reveal that all of the acceptor sites and splice donors D2-D4 are suboptimal due to non-consensus core splicing signals (4, 5). Proper spliced ratios are therefore established via auxiliary cis RNA features, collectively known as splicing regulatory elements. Splicing regulatory elements function either as enhancers or silencers of splicing by recruiting host proteins belonging to the serine-arginine-rich (SR) and hnRNP families, respectively. Splicing regulatory element location (intronic or exonic) influences how frequently a given splice site is utilized, thereby making it difficult to determine general rules of the mechanisms that regulate alternative splicing (6).Splicing from site D4 to A7 removes the Rev-responsive element, which leads to the accu...

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Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

Cited by 30 publications

References 92 publications

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

Solution Structure of the HIV-1 Intron Splicing Silencer and Its Interactions with the UP1 Domain of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1

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