Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial

Haynes, Barton F.; Gilbert, Peter B.; McElrath, M. Juliana; Zolla‐Pazner, Susan; Tomaras, Georgia D.; Alam, S. Munir; Evans, David T.; Montefiori, David C.; Karnasuta, Chitraporn; Sutthent, Reungpung; Liao, Hua Xin; DeVico, Anthony L.; Lewis, George K.; Williams, Constance; Pinter, Abraham; Fong, Youyi; Janes, Holly; deCamp, Allan C.; Huang, Yunda; Rao, Mangala; Billings, Erik; Karasavvas, Nicos; Robb, Merlin L.; Ngauy, Viseth; Souza, Mark S. de; Paris, Robert; Ferrari, Guido; Bailer, Robert T.; Soderberg, Kelly A.; Andrews, Charla; Berman, Phillip W.; Frahm, Nicole; Rosa, Stephen C. De; Alpert, Michael D.; Yates, Nicole L.; Shen, Xiaoying; Koup, Richard A.; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Rerks-Ngarm, Supachai; Michael, Nelson L.; Kim, Jerome H.

doi:10.1056/nejmoa1113425

Cited by 1,661 publications

(2,286 citation statements)

References 38 publications

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“…CRF01_AE is the predominant circulating strain in Thailand, where the RV144 clinical vaccine trial took place. In this trial, which resulted in a modest degree of clinical protection, ADCC responses were identified as a correlate of protection (28), raising the intriguing possibility that naturally occurring His 375 in CRF01_AE Env might have contributed to this outcome. Here we explored the influence of the integrity of the Phe 43 cavity on ADCC responses.…”

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confidence: 89%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

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Zoubchenok

Richard

et al. 2017

J Virol

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibodydependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_ AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.

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confidence: 89%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Prévost

Zoubchenok

Richard

et al. 2017

J Virol

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“…The vaccine demonstrated an efficacy of 31·2% 89. Protection correlated with high levels of anti‐viral IgG, dependent on CD4 T‐cell responses, while vaccine‐driven IgA was associated with an increased risk of infection 90, 91, 92. Immune protection to this highly diverse virus is thought to require broadly neutralizing antibodies (bnAbs) that recognize more conserved regions of the virus 93.…”

Section: Human Vaccines: Recent Progress and Continuing Challengesmentioning

confidence: 99%

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

2018

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SummaryImmunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T‐cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T‐cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include human immunodeficiency virus (HIV), tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T‐cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T‐cells, we need to understand how memory CD4 T‐cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T‐cells that are found in peripheral tissues (tissue resident memory T‐cells) and in the circulation (central and effector memory T‐cells). We discuss the generation of these cells, and the evidence that demonstrates how they provide immune protection in animal and human challenge models.

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“…A correlates analysis revealed that IgG responses to variable regions 1 and 2 (V1‐V2) of Env associated with a decreased infection risk, while IgA responses were associated with an increased risk of infection acquisition 206, 207. Interestingly, IgG responses to V1‐V2 were higher and were associated with a decreased risk of infection acquisition only in individuals with the HLA‐DPB1*13 class II allele, while Env‐specific IgA responses were associated with an enhanced infection risk only in individuals with HLA‐DQB1*06, two class II alleles that were both common (present at frequencies of >10%) in the RV144 vaccine trial participants 208.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial

Cited by 1,661 publications

References 38 publications

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

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