Optimizing antigen design may improve HIV vaccine efforts

From the Pancera, McElrath and Stamatatos labs, Vaccine and Infectious Disease and Clinical Research Divisions

In 1981, the first US cases of what is now known as the acquired immunodeficiency syndrome (AIDS) were diagnosed in California and New York. The confusion and shock that must have followed upon seeing healthy, young men who have sex with men becoming ill with pneumonia or developing a rare type of sarcoma. These men succumbed to their illnesses due to crippled immune systems and no one knew why. The virus causing AIDS, HIV-1, was discovered in 1983 and treatments targeting HIV-1 were implemented starting in 1987. With subsequent optimization over the years, these therapies proved to be successful in reducing AIDS-related symptoms in HIV-1 infected individuals. Yet, the goal for generating a vaccine to prevent HIV-1 establishment in new individuals is ongoing. In the past 10 years, an increasing interest developed for a specific class of antibodies shown to broadly neutralize HIV-1. This antibody class is referred to as “VRC01” and is characterized by a long and complex maturation process which generates antibodies with many sequence changes from the antigen-binding epitope coded for in the germline or original naïve B cell. Several VRC01 antibodies were isolated from individuals with chronic HIV-1 infections. These antibodies bind the envelop (Env) protein located on the outside of the virus particle and neutralize the virus before it enters an uninfected cell. Researchers from the McElrath lab posed the question: Are HIV-1 broadly neutralizing VRC01 antibodies produced following vaccination with the HIV-1 Env protein? Although rare, these researchers isolated a single antibody, FH1, with sequence similarities to known VRC01 antibodies. Researchers from the Stamatatos and Pancera labs determined its structure and characterized its binding properties. Their collaborative findings were published recently in Science Advances.

Antibody maturation occurs generally through the following steps: 1) Naïve B cell receptors interact with an antigen; 2) The activated naïve B cell that recognizes the antigen divides to make more cells that become either antigen-sensing memory B cells or antibody-producing plasma cells; 3) Memory B cells that recognize an antigen follow the same division as naïve B cells into additional memory B cells or plasma cells. Additionally, an important aspect of antibody maturation is mutational variation. The germline sequences encode the antigen-binding epitopes of the naïve B cell receptors (BCRs), but as the B cells differentiate, mutations in these antigen-binding epitopes can occur to alter antigen specificity. This process can help hone the binding specificities of antibodies to a specific, stable antigen or to a “moving target” antigen that changes over time, as may occur for HIV-1 Env during a chronic infection. For the HIV-1 specific broadly neutralizing VRC01 antibodies, the antigen-binding amino acid sequences are quite distinct from the germline ones following chronic HIV-1 infection. These specific VRC01 antibodies mutate at a rate of ~2 substitutions per 100 nucleotides per year in a continuous fashion, which coincides with HIV-1 evolution. While these VRC01 class antibodies are of great interest due to their broadly neutralizing function of HIV-1, it was not previously feasible to determine if current vaccine strategies elicit maturation of HIV-1 specific VRC01 class antibodies. However, Dr. Stamatatos shared that recent “technological advances in the high-throughput isolation of B cells and the sequencing of their BCRs led to the structural and functional characterization of many potent neutralizing antibodies against diverse pathogens.”

These technological advances in studying BCRs were employed by the McElrath lab to, in a high-throughput manner, isolate B cells and sequence hundreds of BCRs from 14 vaccine recipients. These studies led to the discovery of a single antibody, FH1, with amino acid sequence characteristics similar to VRC01 antibodies. Interestingly, the characterization of FH1 by the Stamatatos and Pancera labs revealed that the antibody binds a completely different epitope than all other Env-specific VRC01 antibodies. Specifically, the FH1 binds the C1C2 region of Env, a site similarly bound to by antibodies that activate antibody-dependent cellular cytotoxicity (ADCC). Conversely, previously identified VRC01 antibodies isolated from individuals with chronic HIV-1 infections interact with the CD4-binding domain of Env to neutralize HIV-1. Therefore, “the study reveals that B cells that produce non-neutralizing antibodies [e.g. FH1] may have similar ontogenies to those of potent [VRC01] neutralizing antibodies, bind to different epitopes on the same [Env] antigen as the neutralizing antibodies, and be activated during vaccination,” summarized Dr. Stamatatos.

The broadly neutralizing Env-specific VRC01 class antibodies and the non-neutralizing FH1 antibody are derived from the pairing of the same heavy and light chains that make up the antibody protein structure. Yet, these genetically similar antibodies bind distinct epitopes on the HIV-1 Env protein.
The broadly neutralizing Env-specific VRC01 class antibodies and the non-neutralizing FH1 antibody are derived from the pairing of the same heavy and light chains that make up the antibody protein structure. Yet, these genetically similar antibodies bind distinct epitopes on the HIV-1 Env protein. Figure provided by Dr. Leo Stamatatos (Structures and models generated by the Pancera group)

For future research directions Dr. Stamatatos shared, “we would like to find out whether the epitope-specificities of some non-neutralizing antibodies change during infection or by vaccination.” Understanding the process by which VRC01 class antibodies mature to neutralize HIV-1 and how to elicit this specific response by using variations of Env antigen will be necessary to determine if a VRC01 class antibody response to immunization with Env is a feasible vaccination strategy.

The spotlighted research was funded by the National Institutes of Health.

UW/Fred Hutch Cancer Consortium member Julie McElrath contributed to this work.

Gray MD, Feng J, Weidle CE, Cohen KW, Ballweber-Fleming L, MacCamy AJ, Huynh CN, Trichka JJ, Montefiori D, Ferrari G, Pancera M, McElrath MJ, Stamatatos L. 2022. Characterization of a vaccine-elicited human antibody with sequence homology to VRC01-class antibodies that binds the C1C2 gp120 domain. Sci Adv. 8(18):eabm3948.