HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4
            <sup>+</sup>
            T Cell Responses

Ranasinghe, Srinika; Soghoian, Damien Z.; Lindqvist, Madelene; Ghebremichael, Musie; Donaghey, Faith; Carrington, Mary; Seaman, Michael S.; Kaufmann, Daniel E.; Walker, Bruce D.; Porichis, Filippos

doi:10.1128/jvi.02278-15

Cited by 29 publications

(40 citation statements)

References 42 publications

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“…This unlinked recognition can result in germinal center formation, hypersomatic mutation, and the generation of strongly neutralizing antibodies (39). Evidence for this model has been shown previously in studies describing the correlation of strongly neutralizing antibodies against the HIV-1 envelope with CD4 T-cell recognition of Gag epitopes (40) and the enhancement of antihemagglutinin-specific antibody responses by the adoptive transfer of CD4 T cells that recognized influenza virus matrix and nucleocapsid proteins (39); also, the expres-…”

Section: Discussionmentioning

confidence: 94%

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

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The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM.IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro. The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

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Section: Discussionmentioning

confidence: 94%

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

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“…Additionally, we incorporated a promiscuous T-cell TT epitope to harness the MHC-II antigen presentation pathway that has been shown as a major limiting factor in MPER responses in murine models37. Likewise, in a cohort of untreated HIV-1 infected viremic controllers it has been recently shown an association between gp41-specific CD4 T cell responses with the magnitude and breadth of anti-Env neutralizing antibodies63. We incorporated gp41-MinTT protein into liposomes of diverse composition.…”

Section: Discussionmentioning

confidence: 99%

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Molinos-Albert

Bilbao

Agulló

et al. 2017

Sci Rep

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The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

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“…While elevated percentages of CD8 + CD57 + T cells have been described as a symptom of chronic immune activation [48] and of accelerated immune senescence in chronic HIV infection [49], several studies have also shown that CD8 + CD57 + T cells elicit potent cytotoxic effector functions in HIV and other viral infections [50,51] through high expression of perforin and secretion of IFN-γ and TNF-α [52]. A recent study comparing HIV-specific T cell responses in neutralizers and non-neutralizers showed a greater breadth and magnitude of CD4 + T cell responses to HIV Gag by ELISPOT in neutralizers versus non-neutralizers [37], suggesting a more effective CD4 T cell response. In addition, our data showing that CD8 + CD57 + T cell frequencies correlated positively with total CD8 + T cell frequency and negatively with CD4 + CD25 + T cell frequencies may indicate that elevated frequencies of CD8 + CD57 + T cells in VC with high neutralization breadth reflect reduced T regulatory and increased cytotoxic T cell frequencies in these subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, this group was further subdivided according to the median, and subjects with breadth of 1 to 4 were classified as low-neutralizers ( n =18), and subjects with breadth ≥5 were classified as high neutralizers (neutralizers; n =14). Similar stratifications have been applied previously [37–41]. Neutralization groups were matched for gender, age, ethnicity, time since HIV diagnosis and prior use of cART (Table 1).…”

Section: Methodsmentioning

confidence: 99%

Increased frequencies of CD8⁺CD57⁺ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers

Palmer

Romero-Tejeda

Scully

et al. 2016

Journal of the International AIDS Society

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IntroductionAn effective prophylactic vaccine against HIV will need to elicit antibody responses capable of recognizing and neutralizing rapidly evolving antigenic regions. The immunologic milieu associated with development of neutralizing antibody breadth remains to be fully defined. In this study, we sought to identify immunological signatures associated with neutralization breadth in HIV controllers. We applied an immune monitoring approach to analyze markers of T cell and myeloid cell activation by flow cytometry, comparing broad neutralizers with low- and non-neutralizers using multivariate and univariate analyses.MethodsAntibody neutralization breadth was determined, and cryopreserved peripheral blood mononuclear cells were stained for T cell and myeloid cell activation markers. Subjects were grouped according to neutralization breadth, and T cell and myeloid cell activation was analyzed by partial least squares discriminant analysis to determine immune signatures associated with high neutralization breadth.ResultsWe show that neutralization breadth in HIV viraemic controllers (VC) was strongly associated with increased frequencies of CD8+CD57+ T cells and that this association was independent of viral load, CD4 count and time since HIV diagnosis.ConclusionsOur data show elevated frequencies of CD8+CD57+ T cells in VC who develop neutralization breadth against HIV. This immune signature could serve as a potential biomarker of neutralization breadth and should be further investigated in other HIV-positive cohorts and in HIV vaccine trials.

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HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4 ⁺ T Cell Responses

Abstract: Antigen-specific CD4

Cited by 29 publications

References 42 publications

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Increased frequencies of CD8⁺CD57⁺ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers

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HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4 + T Cell Responses

Abstract: Antigen-specific CD4

Cited by 29 publications

References 42 publications

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Increased frequencies of CD8+CD57+ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers

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Product

Resources

About

HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4 ⁺ T Cell Responses

Increased frequencies of CD8⁺CD57⁺ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers