The secret to an effective HIV vaccine might lie in an unexpected place – the core of the hepatitis B virus.
Imagine your body's immune system as a sophisticated military operation. Some soldiers (B-cells) produce antibodies to tag invaders. Others (T-cells) coordinate the response or directly eliminate infected cells. For decades, HIV researchers have faced a crucial challenge: how to train this military specifically to recognize and eliminate HIV, which has evolved cunning ways to evade detection.
Now, imagine discovering that an unrelated component—a protein from a completely different virus—could dramatically improve your military's training program. This isn't science fiction. Cuban scientists at the Center for Genetic Engineering and Biotechnology have developed a groundbreaking HIV vaccine candidate called TERAVAC that harnesses the power of a hepatitis B virus protein to supercharge the immune response against HIV. Their research reveals how the strategic partnership between two viral proteins—CR3 from HIV and HBcAg from hepatitis B—creates an immune response powerful enough to potentially overcome one of medicine's most elusive foes.
TERAVAC uses hepatitis B core antigen (HBcAg) to enhance the immune response against HIV antigens, creating a more effective vaccine candidate.
To appreciate TERAVAC's breakthrough, we need to understand two key immune system components: Th1 cells and cytotoxic T lymphocytes (CTLs).
Th1 cells act as the "directors" of the immune response. They secrete chemical messengers like interferon-gamma (IFN-γ) that coordinate attacks against intracellular pathogens like viruses. More importantly, they provide essential help to activate CTLs.
CTLs possess the unique ability to identify and eliminate virus-infected cells, cutting off viral production at its source 3 . For HIV, generating strong CTL responses is particularly crucial since the virus hides within cells.
Enter HBcAg—the hepatitis B core antigen. This isn't just any viral protein; it forms virus-like particles (VLPs) that the immune system recognizes as dangerous invaders. Research has shown that HBcAg is remarkably effective at stimulating Th1-type responses 2 4 . When combined with HIV antigens, HBcAg acts as a powerful Th1-biasing adjuvant—essentially a direction signal that tells the immune system: "Attack with Th1 and CTL forces!" 9
The TERAVAC vaccine represents a novel multiantigenic approach. It contains three key components:
A recombinant HIV protein containing multiple Th and CTL epitopes from different HIV proteins
The core antigen from hepatitis B that forms virus-like particles
The surface antigen from hepatitis B 1
The Cuban research team designed a crucial experiment to unravel exactly how these components interact to produce such a potent immune response. The central question: Is it simply the presence of these antigens together that matters, or are there specific interactions driving the enhanced immunity?
The researchers designed a meticulous study using Balb/c mice, following this experimental process 1 :
The team prepared different mixtures of the vaccine components: CR3 alone, CR3 with HBcAg, CR3 with HBsAg, and the complete TERAVAC formulation (CR3 + HBcAg + HBsAg). All formulations were adsorbed onto alum adjuvant.
Groups of mice received subcutaneous immunizations with these different mixtures at anatomical distal sites. This allowed the researchers to compare how each combination affected the immune response.
After the final immunization, the team conducted comprehensive analyses:
The findings revealed a striking pattern: the combination of CR3 with HBcAg produced the most robust Th1-biased immune response. Key results included 1 :
Mice immunized with CR3 and HBcAg showed significantly higher numbers of IFN-γ-secreting cells compared to other combinations
This combination stimulated the strongest proliferation of CD8+ T cells—the crucial CTLs that eliminate infected cells
Higher levels of IgG2a antibodies (associated with Th1 responses) were detected, with minimal production of Th2-associated antibodies (IL-4 and IL-10)
Most importantly, the researchers discovered that non-covalent interactions between CR3 and HBcAg during the adjuvation process were crucial for achieving this optimal immune deviation toward a Th1 response 1 .
| Antigen Combination | IFN-γ Secreting Cells | CD8+ T Cell Proliferation | Th1/Th2 Bias |
|---|---|---|---|
| CR3 alone | Moderate | Low | Mixed |
| CR3 + HBsAg | Moderate | Moderate | Mixed |
| CR3 + HBcAg | High | High | Strong Th1 |
| CR3 + HBcAg + HBsAg | High | High | Strong Th1 |
| Immunization Route | Mucosal Immunity | Systemic Immunity | Th1 Bias |
|---|---|---|---|
| Subcutaneous (s.c.) only | Low | High | Strong |
| Intranasal (i.n.) only | High | Moderate | Moderate |
| Simultaneous s.c. + i.n. | High | High | Strong |
| Adjuvant | Th1 Response | CTL Induction | Mucosal Immunity |
|---|---|---|---|
| Aluminum hydroxide | Weak | Low | No |
| IMS 4112 | Moderate | Moderate | Moderate |
| HBcAg VLP | Strong | Strong | Yes |
| Research Reagent | Function in Experiment |
|---|---|
| Recombinant CR3 protein | HIV-derived chimeric antigen containing multiple T-cell and B-cell epitopes; the primary target for protective immunity |
| HBcAg virus-like particles | Particulate hepatitis B core antigen that acts as both antigen and Th1-biasing adjuvant; enhances CD8+ T cell responses |
| HBsAg | Hepatitis B surface antigen; provides additional epitopes and may contribute to particle formation |
| Aluminum hydroxide (AlOOH) | Traditional adjuvant that helps stimulate initial immune response; used for subcutaneous immunizations |
| ELISPOT assay | Critical technique for detecting and quantifying IFN-γ-secreting T cells; measures Th1 response magnitude |
| CFSE proliferation assay | Fluorescent cell-tracking method that allows monitoring of T cell division in response to antigen stimulation |
The discovery that specific interactions between CR3 and HBcAg drive the enhanced immune response has profound implications for vaccine design. It suggests that future vaccines can be engineered to maximize these beneficial interactions, potentially leading to more effective HIV vaccines.
The TERAVAC approach represents a significant shift from conventional strategies. As one study noted, "the multiantigenic formulation TERAVAC-HIV-1 in Balb/c mice" demonstrated the ability to shift immune responses from the less effective Th2 type to the more protective Th1 type, even in the presence of an established Th2 environment 3 . This is crucial for therapeutic vaccination of already-infected individuals.
Furthermore, recent advances in vaccine stabilization have shown that HBcAg can be formulated to resist high temperatures, maintaining its immunogenicity even without constant refrigeration 6 . This could make such vaccines more accessible in developing regions where HIV burden is highest.
The road to an effective HIV vaccine remains challenging, but the TERAVAC research illuminates a promising path forward. By harnessing the innate immunogenic properties of one virus to target another, scientists are developing creative strategies to outsmart one of medicine's most formidable opponents. As research continues, each discovery brings us closer to the ultimate goal: a world free from HIV/AIDS.