Breakthrough Virus Neutralization Resistance as a Correlate of Protection in a Nonhuman Primate Heterologous Simian Immunodeficiency Virus Vaccine Challenge Study

Lee, Fang-Hua; Mason, Rosemarie D.; Welles, Hugh C.; Learn, Gerald H.; Keele, Brandon F.; Bar, Katharine J.

doi:10.1128/jvi.01531-15

Cited by 11 publications

(9 citation statements)

References 57 publications

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“…It is important to note that the trials analyzed here used entirely different vaccination strategies and challenge stocks from the Roederer et al study, which could explain the inconsistencies between our observations. Nevertheless, our findings do argue against positions 45 and 47 being a universal marker for neutralization resistance (14,36,37,39,40).…”

Section: Discussioncontrasting

confidence: 42%

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Smith

Kilgore

Kasturi

et al. 2016

J Virol

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Mucosal surfaces are vulnerable to human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection IMPORTANCEMost HIV-1 infections occur across a mucosal barrier, and it is therefore important to understand why these sites are vulnerable and how to protect them with a vaccine. To gain insight into these questions, we studied rhesus macaques that were vaccinated with SIVmac239 and unvaccinated controls to determine whether the SIVsmE660 viral variants that infected these two groups were different. We did not find differences between viral variants in the absence versus presence of vaccination-induced immunity, but we did find that the SIVsmE660 viral variants that infected the monkeys, regardless of vaccination, were different from the dominant population found in the viral challenge inoculum. Our data suggest that the mucosal environments of the vagina and rectum both impose a strong selection for the SIVsmE660 variants in the challenge inoculum that are most like SIV and HIVs that circulate in nature.T he majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur across the genital or rectal mucosa and involve a reduction in the diversity of the infecting viral quasispecies (1). This genetic bottleneck of HIV-1 transmission has been attributed to various features of the HIV-1 envelope (Env) glycoproteins (2-8), resistance to interferon (7, 9), and a selection bias toward consensus residues that confer increased in vivo fitness (10). These studies notwithstanding, it has been difficult to pinpoint the attributes that directly facilitate transmission of a particular HIV-1 variant from a genetically diverse quasispecies. A primary focus of nonhuman primate simian immunodeficiency virus (SIV) challenge models is therefore to recapitulate the critical events that occur during HIV-1 transmission so that any observed effect, including protection, is accurately reflected by the model. An approach in which rhesus macaques are inoculated intravaginally or intrarectally at regular intervals with a relatively low dose of SIV has been shown to recapitulate the hallmark reduction in viral diversity characteristic of HIV-1 transmission (11)(12)(13)(14). As a result, the repeated, low-dose challenge method has become widely accepted and commonly utilized to model protection against mucosal SIV infection (14-32). Despite these numerous studies, the characteristics of the virus that influence intravaginal and intrarectal transmission and protection are incompletely understood.We previously demonstrated that an SIVmac239-based regimen consisting of two DNA primes followed by two modified vaccinia virus Ankara (MVA) boosts provided significant protection against repeated, low-dose SIVsmE660 intrarectal challenge. Including granulocyte-macrophage colony-stimulating factor (GM-CSF) or CD40 ligand (CD40L) as an adjuvant with the DNA Citation Smith SA, Kilgore KM, Kasturi SP, Pulendran B, Hunter E, Amara RR, Derdeyn CA. 2016. Signatures in simian immunodeficiency virus SIVsmE660 envelop...

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Section: Discussioncontrasting

confidence: 42%

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Smith

Kilgore

Kasturi

et al. 2016

J Virol

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“…It is important to note that all 8 T/F IMCs have the canonical primer binding site sequence, as well as the optimal version of the other 3 mutations found in the Pol and Env genes of SIVmac239 (37). Additionally, we recently described a viral genotype in SIVsmE660 that is enriched in neutralization-sensitive clones (22,61). In 6 of 8 new clones reported here, there is an A/K at positions 45/47 of envelope, which has been reported as a neutralization-resistant genotype in SIVsmE660 lineage viruses (22).…”

Section: Discussionmentioning

confidence: 99%

Derivation and Characterization of Pathogenic Transmitted/Founder Molecular Clones from Simian Immunodeficiency Virus SIVsmE660 and SIVmac251 following Mucosal Infection

Lopker

Prete

Estes

et al. 2016

J Virol

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Currently available simian immunodeficiency virus (SIV) infectious molecular clones (IMCs) and isolates used in nonhuman primate (NHP) models of AIDS were originally derived from infected macaques during chronic infection or end stage disease and may not authentically recapitulate features of transmitted/founder (T/F) genomes that are of particular interest in transmission, pathogenesis, prevention, and treatment studies. We therefore generated and characterized T/F IMCs from genetically and biologically heterogeneous challenge stocks of SIVmac251 and SIVsmE660. Single-genome amplification (SGA) was used to identify full-length T/F genomes present in plasma during acute infection resulting from atraumatic rectal inoculation of Indian rhesus macaques with low doses of SIVmac251 or SIVsmE660. All 8 T/F clones yielded viruses that were infectious and replication competent in vitro, with replication kinetics similar to those of the widely used chronic-infection-derived IMCs SIVmac239 and SIVsmE543. Phenotypically, the new T/F virus strains exhibited a range of neutralization sensitivity profiles. Four T/F virus strains were inoculated into rhesus macaques, and each exhibited typical SIV replication kinetics. The SIVsm T/F viruses were sensitive to TRIM5␣ restriction. All T/F viruses were pathogenic in rhesus macaques, resulting in progressive CD4؉ T cell loss in gastrointestinal tissues, peripheral blood, and lymphatic tissues. The animals developed pathological immune activation; lymphoid tissue damage, including fibrosis; and clinically significant immunodeficiency leading to AIDS-defining clinical endpoints. These T/F clones represent a new molecular platform for the analysis of virus transmission and immunopathogenesis and for the generation of novel "bar-coded" challenge viruses and next-generation simianhuman immunodeficiency viruses that may advance the HIV/AIDS vaccine agenda. IMPORTANCENonhuman primate research has relied on only a few infectious molecular clones for a myriad of diverse research projects, including pathogenesis, preclinical vaccine evaluations, transmission, and host-versus-pathogen interactions. With new data suggesting a selected phenotype of the virus that causes infection (i.e., the transmitted/founder virus), we sought to generate and characterize infectious molecular clones from two widely used simian immunodeficiency virus lineages (SIVmac251 and SIVsmE660). Although the exact requirements necessary to be a T/F virus are not yet fully understood, we generated cloned viruses with all the necessary characteristic of a successful T/F virus. The cloned viruses revealed typical acute and set point viral-load dynamics with pathological immune activation, lymphoid tissue damage progressing to significant immunodeficiency, and AIDS-defining clinical endpoints in some animals. These T/F clones represent a new molecular platform for studies requiring authentic T/F viruses.

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“…Perhaps the most striking feature of T/F variants is that they are consistently marked by signature amino acid residues IAKN at positions 33, 55, 64, and 88 (HXB2 numbering) in the C1 region of gp120 where A55 and N88 are completely conserved across SIV, SHIV, and HIV‐1 T/F variants in both naïve and immune hosts . Currently, connections between T/F variants and humoral immunity are studied mainly in the context of neutralizing epitopes and their structure on the T/F envelope.…”

Section: Antibody‐mediated Protection Against Hiv‐1: the Neutralizingmentioning

confidence: 99%

“…Third, the neutralization only approach does not address the significance of emerging T/F signatures in the HIV‐1 envelope amino acid sequence . These signatures may have functional and structural significance in the gp120‐gp41 interaction and associated replicative capacity but are not direct targets of potent broadly neutralizing antibodies .…”

Section: Antibody‐mediated Protection Against Hiv‐1: the Neutralizingmentioning

confidence: 99%

Survivors Remorse: antibody‐mediated protection against HIV‐1

Lewis

Pazgier

DeVico

2017

Immunological Reviews

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Summary It is clear that antibodies can play a pivotal role in preventing the transmission of HIV-1 and large efforts to identify an effective antibody-based vaccine to quell the epidemic. Shortly after HIV-1 was discovered as the cause of AIDS, the search for epitopes recognized by neutralizing antibodies became the driving strategy for an antibody-based vaccine. Neutralization escape variants were discovered shortly thereafter, and, after almost three decades of investigation, it is now known that autologous neutralizing antibody responses and their selection of neutralization resistant HIV-1 variants can lead to broadly neutralizing antibodies in some infected individuals. This observation drives an intensive effort to identify a vaccine to elicit broadly neutralizing antibodies. In contrast, there has been less systematic study of antibody specificities that must rely mainly or exclusively on other protective mechanisms, although non-human primate (NHP) studies as well as the RV144 vaccine trial indicate that non-neutralizing antibodies can contribute to protection. Here we propose a novel strategy to identify new epitope targets recognized by these antibodies for which viral escape is unlikely or impossible.

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Breakthrough Virus Neutralization Resistance as a Correlate of Protection in a Nonhuman Primate Heterologous Simian Immunodeficiency Virus Vaccine Challenge Study

Cited by 11 publications

References 57 publications

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Derivation and Characterization of Pathogenic Transmitted/Founder Molecular Clones from Simian Immunodeficiency Virus SIVsmE660 and SIVmac251 following Mucosal Infection

Survivors Remorse: antibody‐mediated protection against HIV‐1

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