Conformational Masking and Receptor-Dependent Unmasking of Highly Conserved Env Epitopes Recognized by Non-Neutralizing Antibodies That Mediate Potent ADCC against HIV-1 (original) (raw)

Antibodies to HIV-1: aiming at the right target

Trends in Microbiology, 2007

HIV-1 evades antibody-mediated neutralization in many cunning ways. The recent structural characterization of a conserved neutralization epitope on the envelope glycoprotein complex (Env) provides clues to the vulnerabilities of the virus. We discuss these observations and explain their relevance for HIV-1 vaccine design.

Challenges of antibody-mediated protection against HIV-1

Expert Review of Vaccines, 2010

Enthusiasm for a role of antibodies in protection against HIV-1 has waxed and waned over the 25-year search for an AIDS vaccine. However, it is now clear that antibodies not only contribute to the control of infection once it is established [1,2], as a series of seminal passive immunization studies in nonhuman primates (NHPs) going back almost 20 years show unequivocally that antibodies can prevent infection with model AIDS viruses [3-14]. These latter observations are currently driving an intense effort to identify epitopes recognized by broadly neutralizing monoclonal antibodies (mAbs) to serve as templates for AIDS vaccine design. To this end, a handful of broadly neutralizing mAbs have been successfully vetted in passive immunization studies in NHPs using SHIVs that are model simian immuno-deficiency viruses (SIV) in which the SIV envelope glycoprotein (Env) is replaced by a HIV-1 Env glycoprotein. The Env glycoprotein is the only HIV-1 protein known to be recognized by neutralizing antibodies. These studies show that SHIV infection can be blocked by individual mAbs specific for epitopes associated with distinct regions of the HIV-1 Env protein. These include the CD4-binding site [9,15] and high-mannose oligosaccharides [7,16] of gp120, as well as the membrane proximal region of gp41 [17]. It should be noted that while individual mAbs can be effective, mAb mixtures [7,18] or neutralizing sera [19,20] might be more potent. Collectively, these studies strongly argue that the correct antibodies can mediate sterilizing (i.e., transmission-blocking) immunity to HIV-1 and that an AIDS vaccine must elicit such antibodies to be effective. There are three key challenges to the development of an 'antibody-based' vaccine that are potentially solvable with the experimental tools currently in hand. Identification of epitopes recognized by broadly neutralizing antibodies Extreme genetic diversity is a hallmark of retroviral infections, including HIV-1, which surfaces as a significant and long-recognized antigenic diversity problem in AIDS vaccine development [21-25]. For example, there are 12 distinct clades (genetic subtypes) of HIV-1

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

Immunity, 2019

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448 gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

Unlocking HIV-1 Env: implications for antibody attack

AIDS Research and Therapy, 2017

Collective evidence supporting a role of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in controlling HIV-1 transmission and disease progression emerged in the last few years. Non-neutralizing antibodies (nnAbs) recognizing conserved CD4-induced epitopes on Env and able to mediate potent ADCC against HIV-1-infected cells exposing Env in its CD4-bound conformation have been shown to be present in some RV144 vaccinees and most HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to decrease exposure of this Env conformation by downregulating CD4 and by limiting the overall amount of cell-surface Env. In this review, we will summarize our contribution to this rapidly evolving field, discuss how structural properties of HIV-1 Env might have contributed to the modest efficacy of the RV144 trial and how we recently used this knowledge to develop new strategies aimed at sensitizing HIV-1-infected cells to ADCC mediated by easy to elicit nnAbs.

Structural Insights from HIV-Antibody Coevolution and Related Immunization Studies

AIDS research and human retroviruses, 2018

Human immunodeficiency virus type 1 (HIV-1) is a rapidly evolving pathogen that causes acquired immunodeficiency syndrome (AIDS) in humans. There are ∼30-35 million people infected with HIV around the world, and ∼25 million have died since the first reported cases in 1981. In addition, each year 2-3 million people become newly infected, and >1 million die of AIDS. An HIV-1 vaccine would help halt an AIDS pandemic, and efforts to develop a vaccine have focused on targeting the HIV-1 envelope, Env, found on the surface of the virus. A number of chronically infected individuals have been shown to produce antibodies, called broadly neutralizing antibodies (bnAbs), that target many strains of HIV-1 by binding to Env, thus suggesting promise for HIV-1 vaccine development. BnAbs take years to develop, and have a number of traits that inhibit their production; thus, a number of researchers are trying to understand the pathways that result in bnAb production, so that they can be elicited ...

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

Viruses

Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of "classical" vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine.