Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

Liao, Hua‐Xin; Chen, Xi; Munshaw, Supriya; Zhang, Ruijun; Marshall, Dawn J.; Vandergrift, Nathan; Whitesides, John F.; Lu, Xiaozhi; Yu, Jia; Hwang, Kwan‐Ki; Gao, Feng; Markowitz, Martin; Heath, Sonya L.; Bar, Katharine J.; Goepfert, Paul; Montefiori, David C.; Shaw, George; Alam, S. Munir; Margolis, David M.; Denny, Thomas N.; Boyd, Scott D.; Marshal, Eleanor; Egholm, Michael; Simen, Birgitte B.; Hanczaruk, Bozena; Fire, Andrew; Voss, Gérald; Kelsoe, Garnett; Tomaras, Georgia D.; Moody, M. Anthony; Kepler, Thomas B.; Haynes, Barton F.

doi:10.1084/jem.20110363

Cited by 195 publications

(273 citation statements)

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“…Second, the TF Env may not engage the HIV-1 antibody UCA but rather engages latter members of the antibody lineage (Figure 6). We have found this to be the case with commonly made non-broadly neutralizing gp41 Env antibodies that are the first to arise in HIV-1 infection, for which the gp41 lineage was initiated by antigens derived from the microbiome before HIV-1 infection and, upon HIV-1 infection, gp41 Env engaged cross-reactive affinity matured B cells (90–92) (Figure 6). Diversion of pre-existing B cell responses to non-HIV antigens may be at play for some bnAb UCAs as well.…”

Section: B Cell Lineage Immunogen Designmentioning

confidence: 85%

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Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

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Summary Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs. This work has revealed that a virus-antibody “arms race” occurs in which a HIV-1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity-matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host-pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here we review the progress to date in elucidating bnAb B cell lineages in HIV-1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV-1 sequential envelope vaccine candidates.

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Section: B Cell Lineage Immunogen Designmentioning

confidence: 85%

“…Among the microbiota-induced memory B cells, we have demonstrated that some cells can cross-react with HIV gp41 Env (90–92). Transmitted/founder virus Env can engage these mutated cells, even if the unmutated ancestor naïve B could not, and diverge clonal evolution to affinity maturation against Env (green pathway).…”

Section: Figurementioning

confidence: 99%

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

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164

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“…These studies also found no differences in V H use, although, again, the number of sequences studied was small. In contrast, studies have found differences in D segment use between antibodies with short and long CDR3s, including the appearance of tandem D gene segments in very long CDR3s, suggesting a potential causative relationship (4,12). However, these studies did not investigate whether these differences were a sign of selection during B-cell maturation.…”

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confidence: 83%

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Kaplinsky

Sun

et al. 2014

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

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Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (V H )-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in V H gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use V H genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential V H gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.immunomics | principal component analysis | development T he mature antibody repertoire is shaped by selective forces that influence B-cell survival (1). Comparison of immature and mature B-cell subsets has shown that selection acts specifically on complementarity determining region 3 (CDR3) of the antibody heavy-chain molecule, an antigen-binding region that is a key determinant of antigen specificity (2). On average, mature B-cell subsets express antibodies that have shorter and more negatively charged CDR3s, which is the result of selection against autoreactive and polyreactive B cells (3,4).Each recombined antibody heavy-chain gene is composed of a variable (V H ), diversity (D), and joining (J H ) gene segment. Because the CDR3 region spans the V H -D-J H joint, investigators have asked whether selection might favor B cells whose antibodies use specific V H , D, or J H gene segments. Selection in favor of specific gene segments during B-cell maturation might help to explain the observed maturation-associated changes in CDR3 length and charge, and might suggest a preference for "hard-wired" antigen specificities. Evidence against selection would suggest that differences in CDR3 result exclusively from the nontemplated addition and deletion of nucleotides at the V H -D and D-J H junctions, and therefore that the death of B cells with counterselected CDR3s during maturation is simply the evolutionary cost (3) of maintaining this mechanism of generating antibody diversity.Nearly two decades ago, a low-throughput sequencing study in mice suggested that specific V H gene segments were used at different frequencies by pre-B cells (in which heavy-chain recombination has been completed) and mature B cells in the spleen (5). This observation was interpreted as selection for hard-wired specificities. However, the statistical robustness of this observation was limited by the small number of recombined genes that were sequenced, and although subsequent investigations have detected differences in V H use between pre-B and upstream pro-B cells, they have failed to confirm such differences between pre-B and...

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“…The earliest changes to the virus population are driven by the CD8 + T‐cell response that is induced as viremia increases39 and places strong selection pressure on the virus, resulting in complete turnover of the virus pool within the first few weeks of infection 40. The development of antibody responses follows a pattern, with antiviral antibodies being detected first as immune complexes41 followed by free antibody directed at the HIV‐1 envelope (Env) glycoprotein 41 (gp41) subunit,41, 42 and then by the development of Env glycoprotein 120 (gp120)‐binding antibodies 41. These early antibody responses do not neutralize or place selective pressure on virus evolution41; antibodies capable of neutralizing autologous viruses are not detectable until weeks to months after infection is established19, 20 and have little to no activity against heterologous HIV‐1 strains 43.…”

Section: Development Of Broadly Neutralizing Antibodies In Hiv‐1 Infementioning

confidence: 99%

“…It is possible that trafficking of the negative regulatory factor (Nef) protein from HIV‐1‐infected macrophages to B cells may alter class switching and germinal center (GC) responses,58 but dysfunction is also likely driven by the early cytokine storm59 and ongoing immune dysfunction caused by HIV‐1 infection of T cells. B‐cell dysregulation is evidenced by the delayed antibody response in acute HIV‐1 infection,41 an increase in the proportion of activated memory B cells and exhausted B cells, non‐specific plasmablast activation (leading to polyclonal immunoglobulin production), and a decline in the frequency of long‐lived plasma cells 42, 60, 61, 62, 63. In addition, Env‐specific B cells are found in the activated and exhausted B‐cell subsets in viremic individuals 64.…”

Section: Development Of Broadly Neutralizing Antibodies In Hiv‐1 Infementioning

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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Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

Abstract: Many HIV-1 envelope-reactive antibodies shortly after HIV-1 transmission may arise from crow-reactive memory B cells previously stimulated by non-HIV-1 host or microbial antigens

Cited by 195 publications

References 47 publications

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

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

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