Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies

Abstract

After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1-host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success.

Structure-based stabilization of SOSIP Env enhances recombinant ectodomain durability and yield

“…Conventional vaccination efforts have thus far been unable to elicit broadly neutralizing antibodies, which are correlated with protection against HIV-1 acquisition. These failures have prompted the development of new mosaic immunogens and sequential immunization strategies, the latter of which are intended to guide the immune system from germline targeting through the process of antibody maturation (34,35). These proposed vaccination regimens require the production of numerous, diverse Env immunogens, many of which are recalcitrant to recombinant expression despite modification with previously reported stabilization strategies.…”

Humanized V(D)J-rearranging and TdT-expressing Mouse Vaccine Models with Physiological HIV-1 Broadly Neutralizing Antibody Precursors

“…Mouse models expressing a unique bnAb precursor cannot assess this critical parameter. Also, expression of certain bnAb precursors HCs or LCs can interfere with B cell development, leading to B cell deletion in bone marrow or anergy in peripheral lymphoid tissues (71,(73)(74)(75). The prototype VRC01-class rearranging mouse model we have described here, addresses these potential issues in the VRC01 lineage, as V(D)J recombination generates human VRC01-class precursors that express highly diverse CDR3s, many of which may be compatible with bnAb development.…”

Combination anti‐HIV antibodies to achieve antiretroviral therapy‐free virological suppression in infected individuals

“…In this regard, long‐acting injectable antiretroviral drugs hold promise for suppressing plasma viremia with infrequent dosing 7–9 . In addition, broadly neutralizing monoclonal antibodies (bNAbs) against HIV have emerged as a promising therapeutic modality to achieve durable suppression of plasma viremia for extended periods 10,11 …”

“… 7 , 8 , 9 In addition, broadly neutralizing monoclonal antibodies (bNAbs) against HIV have emerged as a promising therapeutic modality to achieve durable suppression of plasma viremia for extended periods. 10 , 11 …”

“…[7][8][9] In addition, broadly neutralizing monoclonal antibodies (bNAbs) against HIV have emerged as a promising therapeutic modality to achieve durable suppression of plasma viremia for extended periods. 10,11 The first group of monoclonal antibodies against HIV exhibiting in vitro neutralization activity were described in the early 1990s. 12 Although some of these antibodies showed promising results, subsequent studies in humans generated less favorable outcomes.…”