HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1

Schoofs, Till; Klein, Florian; Braunschweig, Malte; Kreider, Edward F.; Feldmann, Anna; Nogueira, Lilian; Oliveira, Thiago Y.; Lorenzi, Julio C. C.; Parrish, Erica H.; Learn, Gerald H.; West, Anthony P.; Björkman, Pamela J.; Schlesinger, Sarah J.; Seaman, Michael S.; Czartoski, Julie; McElrath, M. Juliana; Pfeifer, Nico; Hahn, Beatrice H.; Caskey, Marina; Nussenzweig, Michel C.

doi:10.1126/science.aaf0972

Cited by 277 publications

(273 citation statements)

References 52 publications

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“…Whether individuals who have developed bnAbs exhibit a reduced susceptibility to HIV‐1 super‐infection has not been addressed, although as bnAbs constitute only part of the overall HIV‐specific antibody response they may not reach sufficient titers to do so. The lack of clinical impact of bnAbs is consistent with early bnAb infusion studies in animal models68 and humans69 that did not show a lasting impact on HIV‐1 viral loads, although newer, more potent bnAbs appear to have a more persistent impact on viral load70, 71, 72 and subsequent antibody development 73. At this time, ongoing clinical trials are being conducted to determine if bnAb infusion can augment other anti‐HIV‐1 therapies.…”

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

confidence: 62%

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

confidence: 62%

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

Borrow

Moody

2017

Immunological Reviews

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“…Most studies with anti-HIV monoclonal antibodies (MAbs) have examined the neutralization of cell-free virus (1)(2)(3)(4) or the prevention of intercel-lular transmission (5). In reality, MAbs likely exert anti-HIV effects in multiple ways, including by prevention of cellular infection; targeting of infected cells, including FcR-positive cells or complement, for destruction by Fc-mediated effects (6)(7)(8)(9); or delivery of a toxic payload to cells in the form of immunoconjugates (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). It is often assumed that the same MAbs that prevent the transmission of infection are also the most effective in eliminating persistently infected cells (21,22), despite evidence to the contrary (6,13,16,19).…”

Section: Importancementioning

confidence: 99%

“…Purging may be accomplished by the viral cytopathic effect, by established host defenses, or by actively eliminating cells with passively administered MAbs or cytotoxic immunoconjugates (17,20). MAbs may eliminate cells via Fc-mediated mechanisms (8,9), or they may be used in immunoconjugates that kill cells by the delivery of a toxin, small drug, or high-energy radioisotope. We and others have designed ITs targeted to cells expressing HIV Env (10,11,(13)(14)(15)(16)(17)(18)(19)(20)67).…”

Section: Efficacy Of Its Tested On Cells Transfected To Express Cell mentioning

confidence: 99%

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Pincus

Song

Maresh

et al. 2017

J Virol

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The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fcmediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIVinfected cells and eradicate persistent reservoirs of HIV infection.IMPORTANCE There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy.

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“…It has been suggested that MAb administration can boost autologous adaptive immune responses (23,24), presumably by improved antibody-bound antigen delivery to and presentation by DC (22). We therefore measured humoral responses to HIV-1 Env in animals' day 0 and week 22 sera, a time point where N6-LS and PGT121 had been long cleared, against a panel of tier 1 (n ϭ 3) and tier 2 (n ϭ 4) HIV-1 pseudoviruses and the SHIV-SF162P3 challenge stock.…”

Section: Figmentioning

confidence: 99%

Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys

Jülg

Pegu

Abbink

et al. 2017

J Virol

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Passive immunotherapy against HIV-1 will most likely require broadly neutralizing antibodies (bnAbs) with maximum breadth and potency to ensure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross-clade pseudoviruses. We evaluated the in vivo antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically simianhuman immunodeficiency virus (SHIV)-SF162P3-infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7, while the combination of both antibodies suppressed all animals. The combination of both antibodies had no additive antiviral effect compared to a single dose of PGT121, potentially reflecting the nearly 10-fold-higher potency of PGT121 against this SHIV. Viral rebound occurred in the majority of suppressed animals and was linked to declining plasma bnAb levels over time. In addition to the effect on plasma viremia, bnAb administration resulted in significantly reduced proviral DNA levels in PBMCs after 2 weeks and in lymph nodes after 10 weeks. Autologous neutralizing antibody (nAb) responses and CD8 ϩ T-cell responses were not significantly enhanced in the bnAbtreated animals compared to control animals, arguing against their contribution to the viral effects observed. These results confirm the robust antiviral activity of N6-LS in vivo, supporting the further clinical development of this antibody.IMPORTANCE Monocloncal antibodies (MAbs) are being considered for passive immunotherapy of HIV-1 infection. A critical requirement for such strategies is the identification of MAbs that recognize the diversity of variants within circulating but also reservoir viruses, and MAb combinations might be needed to achieve this goal. This study evaluates the novel bnAb N6-LS alone or in combination with the bnAb PGT121, in rhesus macaques that were chronically infected with SHIV. The results demonstrate that N6-LS potently suppressed plasma viral loads in the majority of animals but that the combination with PGT121 was not superior to PGT121 alone in delaying time to viral rebound or reducing peripheral blood mononuclear cell (PBMC) or lymph node proviral DNA levels. The occurrence of viral escape variants in an N6-LS-monotreated animal, however, argues for the need to maximize breadth and antiviral efficacy by combining bnAbs for therapeutic indications.

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HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1

Cited by 277 publications

References 52 publications

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

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

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys

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