From Serotherapy to Modern Therapeutics
The fight against HIV has evolved from early blood-based therapies to sophisticated modern treatments that offer new hope.
In the 1980s, as the AIDS epidemic swept across the globe, scientists were in a race against time to understand and combat this mysterious new virus. Among the many investigative pathways was an approach called serotherapy—a treatment strategy borrowed from cancer therapy that proposed using antibody-rich blood plasma from recovered patients to fight the infection in those newly diagnosed. While this early approach would not become the primary solution, it represented a crucial stepping stone in our understanding of HIV and laid the groundwork for today's revolutionary treatments, including long-acting injectables and broadly neutralizing antibodies that are transforming HIV management.
The concept of serotherapy for AIDS was formally introduced in a 1986 correspondence published in Nature titled "Serotherapy for AIDS and pre-AIDS syndrome." 1 This proposed therapeutic approach suggested using antibody-rich serum from individuals who had developed immune responses to HIV to treat infected patients. The theoretical foundation was straightforward: transfer the protective components of an immune response from a resistant individual to a vulnerable one.
Finding individuals with strong immune responses to HIV
Harvesting plasma containing HIV-specific antibodies
Administering plasma to patients with AIDS or pre-AIDS
Tagging the virus for destruction by the immune system
While this approach showed some early promise and provided valuable insights, it ultimately faced significant limitations. The high variability of HIV strains meant that antibodies from one person often didn't effectively combat the virus in another. Additionally, the quantity of antibodies required for consistent efficacy proved challenging to standardize and produce at scale. Nevertheless, this early investigation into antibody-based therapy planted the seeds for today's more sophisticated approaches using precisely engineered antibodies.
Antibodies, also known as immunoglobulins, are specialized proteins produced by the immune system to identify and neutralize foreign invaders like viruses and bacteria. Each antibody is designed to recognize a specific molecular structure, known as an antigen, on a pathogen's surface.
Binding directly to the virus and preventing it from entering human cells
Tagging viral particles for destruction by other immune cells
Triggering a cascade of immune responses that eliminate the virus
The extraordinary diversity and rapid mutation rate of HIV present particular challenges for antibody-based approaches. The virus's envelope proteins—the primary target for antibodies—are heavily shielded with sugar molecules and constantly changing, making it difficult for naturally produced antibodies to maintain effectiveness. This understanding has driven scientists to develop more sophisticated solutions, including broadly neutralizing antibodies (bNAbs) that target conserved, less variable regions of the virus.
While serotherapy using donor plasma has largely been superseded, its fundamental principle—harnessing the power of antibodies—has reemerged in cutting-edge HIV research and treatment.
Today's approach uses genetically engineered bNAbs that can neutralize a wide range of HIV strains, overcoming the variability that limited early serotherapy:
Recent clinical trials have demonstrated remarkable success with these engineered antibodies. A phase 2 trial presented at EACS 2025 investigated a novel combination therapy of lenacapavir with two bNAbs—teropavimab (TAB) and zinlirvimab (ZAB). The study involved virologically suppressed people living with HIV who were randomized to switch to this new regimen or remain on their stable baseline regimen. At 52 weeks, the results showed that most participants maintained viral suppression, with only three out of 53 in the bNAb group having HIV RNA levels above 50 copies/mL, and no serious adverse events leading to treatment discontinuation 3 .
Another antibody-adjacent approach involves allosteric inhibitors that target HIV proteins indirectly. Pirmitegravir, the first allosteric integrase inhibitor (ALLINI) to demonstrate clinical proof of concept, represents a novel drug class that works by:
In a Phase IIa trial, pirmitegravir achieved significant viral load reductions of -1.55 log₁₀ copies/mL at the 200mg dose after just ten days of treatment in ART-naive adults with HIV-1, confirming that allosteric inhibition of integrase is clinically viable 2 .
| Therapy | Trial Phase | Key Results | Advantages |
|---|---|---|---|
| Pirmitegravir (ALLINI) | Phase IIa | -1.55 log₁₀ viral load reduction (200mg) | Novel mechanism; effective against resistant strains |
| Lenacapavir + TAB + ZAB | Phase II | Maintained viral suppression at 52 weeks | Twice-yearly dosing; well-tolerated |
| Lenacapavir for PrEP | Phase III | 96% risk reduction for HIV acquisition | Superior adherence; transformative for at-risk populations |
Perhaps the most transformative development in HIV management has been the advent of long-acting prevention options, particularly lenacapavir for pre-exposure prophylaxis (PrEP). The PURPOSE-2 clinical trial, led by physicians at Emory University and Grady Health System, demonstrated that a twice-yearly injection of lenacapavir reduced the risk of HIV infection by 96%—significantly more effective than daily oral PrEP options 6 .
"What we see over time is that about half of people who start taking daily oral PrEP stop within a year due to various factors. Having an effective injectable that is only needed twice annually is very significant for people who have trouble accessing health care or staying adherent to daily, oral pills."
This breakthrough is particularly important for addressing adherence challenges and healthcare disparities.
| Method | Dosing Frequency | Key Advantages | Efficacy |
|---|---|---|---|
| Oral PrEP (Truvada) | Daily | Well-established safety profile | ~99% with perfect adherence |
| Injectable Cabotegravir | Every 2 months | Less frequent than daily pills | Higher than oral PrEP |
| Lenacapavir | Every 6 months | Minimal adherence burden | 96% reduction in infection |
| bNAbs (Experimental) | Every 3-6 months | Novel mechanism, high specificity | Under investigation |
| Research Tool | Function | Application in HIV Research |
|---|---|---|
| Broadly Neutralizing Antibodies (bNAbs) | Target conserved regions on HIV envelope | Passive immunization; combination therapies |
| Allosteric Integrase Inhibitors | Disrupt viral assembly via noncatalytic sites | Novel mechanism against resistant strains |
| Long-Acting Formulations | Sustain drug levels over extended periods | Improve adherence through infrequent dosing |
| Anti-HLA Donor-Specific Antibodies | Selectively target donor-derived immune cells | Adapted from transplant medicine for GVHD |
| Viral Load Assays | Quantify HIV RNA copies in blood | Primary endpoint for clinical trial efficacy |
The innovative application of these tools is exemplified by a 2022 study published in Science Direct, where researchers used donor-targeted serotherapy as a rescue therapy for steroid-resistant graft-versus-host disease (GVHD) in transplant patients. This approach used anti-HLA donor-specific antibodies (DSAs) through transfusion of highly selected plasma, which bound to and selectively depleted circulating donor T cells without rejecting the renal allografts. This provided proof of concept for a highly targeted therapeutic approach that could have implications for HIV-related complications 5 .
The journey from the early proposal of serotherapy in 1986 to today's sophisticated antibody-based approaches illustrates how scientific concepts evolve and transform patient care. The future of HIV treatment appears to be moving toward:
Annual or even less frequent dosing regimens
Targeting multiple HIV epitopes simultaneously
Instructing the body to produce its own protective antibodies
mRNA platforms for rapid response to viral mutations
As research continues, the lessons learned from early serotherapy attempts continue to inform new generations of HIV therapeutics. What began as a simple concept—using antibodies to fight infection—has blossomed into a sophisticated field of precision medicine that offers hope for eventually ending the HIV epidemic.
The story of serotherapy for AIDS represents both the creative thinking of scientists facing a mysterious new disease and the iterative nature of medical progress. While the original concept of using donor plasma was ultimately limited, the fundamental insight—that antibodies could be harnessed to fight HIV—has proven remarkably prescient. Today, that insight has evolved into powerful new drug classes and long-acting formulations that are transforming HIV from a fatal diagnosis to a manageable chronic condition for millions worldwide.
The ongoing development of twice-yearly injections, combination therapies with bNAbs, and novel mechanisms like allosteric integrase inhibitors demonstrates how early ideas can mature into revolutionary treatments through persistent scientific inquiry and innovation. As these advances continue, they bring us closer to the ultimate goal: a world without HIV.