Structural Biology Wages War On HIV And The Pandemics Of Tomorrow

By Prem Prakash, Ph.D., research scientist, Department of Microbiology, Immunology and Physiology, Center for AIDS Health Disparities Research, Meharry Medical College

Imagine waking up to news of another outbreak — masks, lockdowns, lives upended. We've all felt that fear from COVID-19, but what if we could stop the next one before it starts? As someone who's lost colleagues to HIV-related complications and seen families torn apart by viruses, I know this isn't just lab work; it's about saving lives. In this article, we'll explore how scientists like me are using "molecular spyglasses" to expose viruses' weak spots. From HIV's hidden hideouts in our cells to the Nipah virus' terrifying speed, these discoveries aren't distant — they're powering vaccines and drugs that could protect your loved ones. Join me on this journey from the atomic battlefield to a virus-proof tomorrow and read how you can be part of the fight.

In a world still reeling from the COVID-19 pandemic and bracing for the next viral outbreak, structural biology emerges as the unsung hero in the fight against deadly viruses. From HIV's persistent reservoirs to the zoonotic threats of Nipah and SARS-CoV-2, atomic-level insights into viral proteins and host interactions are revolutionizing antiviral drug discovery. My work on understanding the mechanisms of HIV-1 integration into the human genome, including the human host enzyme three prime repair exonuclease 1 (TREX1),^1,2 has revealed how subtle structural dynamics can be exploited for novel therapeutic intervention. This article delves into recent breakthroughs, drawing from my research and global studies on infectious diseases, to illustrate how structural biology is arming us against current and future pandemics.

How Tiny Atomic Clues Are Arming Us To Strike Back

HIV-1's ability to integrate its genome into human DNA creates lifelong reservoirs, making a cure elusive despite effective antiretrovirals. Recent structural studies have illuminated this process, offering new drug targets. In my 2024 study, published in the Journal of Biological Chemistry,³ we used structural biology tools, (fluorescence polarization [FP], molecular dynamic simulations [MDS], and biochemical approaches) to show that human TREX1 preferentially degrades integration-incompetent HIV-1 DNA through optimized kinetics and thermodynamics. This work highlights TREX1's exonuclease domain as a key interface for host-virus antagonism.

The impact of this research extends to understanding HIV's innate immune evasion strategies, as evidenced by its citation in a 2025 review.⁴ There, our findings are referenced to explain how TREX1 preferentially degrades integration-incompetent viral DNA, thereby limiting cGAS sensing and enhancing productive infection. This connection underscores the drug discovery potential: by targeting TREX1's structural preferences, we could design small molecules or biologics that stabilize incompetent DNA forms, amplifying cGAS activation to boost innate immunity. Such approaches could lead to novel adjuvants for antiretroviral therapies, reducing viral reservoirs and improving outcomes in people living with HIV (PLWH), while informing broad-spectrum antivirals against other retroviruses.

Building on this further, a 2025 study in Nature revealed integrase's unexpected structural role in HIV maturation, beyond its known function in DNA insertion.⁵ Using cryo-electron microscopy (cryo-EM), an extremely powerful structural biology tool, researchers showed integrase stabilizes the capsid during virion assembly, a discovery that could inspire allosteric inhibitors. Gilead's lenacapavir⁶ disrupts this HIV-1 capsid assembly, preventing infection with six-month efficacy in trials. Structural models of the capsid, derived from all-atom simulations, show its fullerene-like architecture with pentameric and hexameric units, which are so vulnerable to such aforementioned disruptions that it’s enough to combat the progression of HIV-1 in the human body.

Comorbidities like cardiovascular disease and hypertension complicate HIV management. A review I wrote in 2024 explores HIV-associated hypertension, identifying knowledge gaps in risks and mechanisms, such as immune activation and endothelial dysfunction driven by viral persistence. These structural insights into HIV-host interactions, like those from TREX1 and capsid studies, can guide drug designs that minimize inflammatory side effects, potentially reducing hypertension risks in PLWH. Similarly, an HIV analysis forecasts the global burden of HIV/AIDS to 2050,⁷ emphasizing the need for therapies addressing non-AIDS events like heart disease. By integrating epidemiological data with structural biology, we can prioritize targets that tackle both viral replication and long-term cardiovascular complications, as evidenced in a research article I co-authored on global cardiovascular burdens, which links infectious diseases to rising risk factors worldwide.⁸

At the Conference on Retroviruses and Opportunistic Infections (CROI) 2026, Gilead presented Phase 3 data on bictegravir/lenacapavir combinations, showing 96-week suppression and early results from islatravir/lenacapavir for weekly oral regimens. All of these advances are rooted in structural biology and biochemistry and promise to expand treatment options for PLWH facing resistance or adherence issues.

COVID And The Deadly Nipah: What Hidden Weaknesses Have We Found?

Structural biology's toolkit — cryo-EM, X-ray crystallography, molecular dynamics simulation, and AI-driven modeling, such as AlphaFold — extends beyond HIV to other deadly viruses. For SARS-CoV-2, the spike protein's prefusion structure, resolved early in the pandemic, enabled rapid vaccine design. A 2025 open-science collaboration identified ASAP-0017445, a broad-spectrum antiviral that binds the main protease, with promising preclinical safety. The Midwest Antiviral Drug Discovery Center's 2024 work combined structural biology with alpaca-derived nanobodies and phages to target evolving variants, yielding inhibitors against Omicron variants.

Nipah virus, with a 70% fatality rate, poses a potential pandemic risk. Seasonal outbreaks require structural-guided therapies.⁹ A 2024 breakthrough monoclonal antibody, hu1F5, protected nonhuman primates against Nipah, targeting the fusion glycoprotein.⁹ Computational biophysics in 2025 identified procyanidins B2-B7 as high-affinity binders to Nipah's G protein via induced-fit mechanisms.¹⁰ Reverse genetics systems have accelerated antiviral screening, revealing indole scaffolds as privileged anti-Nipah agents.

My research on structural insights into allosteric behavior and catalytic mechanism of key metabolic enzymes¹¹ bridges current cross-viral structural biology applications (e.g., cryo-EM for Ebola's glycoprotein guiding mAb cocktails like REGN-EB3 or Zika's envelope insights for flavivirus inhibitors). I resolved 10 novel crystal structures of glutamate dehydrogenase (GDH) complexes with substrates, intermediates, and inhibitors, unveiling catalytic mechanisms and metabolic regulation in the Krebs cycle.¹¹ These GDH insights demonstrate transferable expertise in X-ray crystallography and molecular dynamics for probing enzyme dynamics and binding sites,¹¹ which may directly apply to viral drug discovery by modeling how viruses (e.g., HIV, Ebola, Zika) reprogram host metabolism for replication. This enables innovative broad-spectrum inhibitors to target metabolic-virus interfaces, highlighting structural biology's cross-disciplinary power.

Tips For Virus Hunting

Despite progress, challenges persist. Viral genetic variability demands broad-spectrum designs; ignoring it leads to narrow efficacy, as seen in early KRAS inhibitors.¹² Over reliance on static structures misses dynamics; try integrating molecular dynamics simulations.

To enhance drug discovery pipelines amid viral variability and dynamic challenges, personnel should prioritize broad-spectrum host-directed therapies like verdinexor analogs for arenaviruses,¹³ integrating molecular dynamics simulations with biophysical assays, isothermal calorimetry (ITC), surface plasmon resonance (SPR), and fluorescence polarization (FP) technique for binding affinity and kinetic profiles. Apply pharmacogenomics by incorporating patient-specific genetic profiling early in clinical trials to optimize oncology regimens like methotrexate in comorbid patients — my take is that this personalized approach¹⁴ not only minimizes toxicities by predicting metabolic variants but also boosts efficacy through adaptive dosing, potentially slashing attrition rates by 20% to 30% based on emerging data from multi-omics integrations.¹⁵ Additionally, pharmacogenomics, like CPIC for HIV ART, personalizes treatments, addressing comorbidities like those in my cardiovascular burden studies.

Here are some additional tips:

• Leverage AI-driven virtual screening for rapid hit-to-lead progression¹⁶
• Incorporate organoids or organ-on-chip models early for accurate predictions
• Diversify compound libraries with AI-optimized natural products to combat resistance
• Emphasize polypharmacology for multi-target drugs in complex diseases
• Foster cross-disciplinary teams with CRISPR functional genomics for robust target validation¹⁷
• Adopt green chemistry principles, like biocatalysis for sustainable synthesis
• Monitor real-world evidence through post-market data integration
• Navigate evolving regulations (e.g., Canada's biologics trials) via proactive compliance audits to streamline ethical, efficient development
• Align with FDA/EMA guidelines for structure-based design (ICH Q11), ensuring GLP-compliant data

What's Next In The Fight Against Pandemics?

AI tools like AlphaFold and deep machine learning accelerate structure prediction, enabling rapid hit identification for pan-viral inhibitors. My chromatin-preintegration complex research points to epigenetic modulators as next-gen antivirals. Oligonucleotide therapies and CRISPR target integration sites, while mRNA platforms repurpose for therapeutics.

The INTREPID Alliance's 2025 pipeline review shows 109 preclinical antivirals across 13 families, with SARS-CoV-2 dominating. Tri-complex inhibitors and proteolysis targeting chimera (PROTACs) degrade undruggable targets. Structural biology is decoding viruses' secrets, from HIV's capsid to Nipah's glycoprotein, fueling therapies that modify disease courses.

My forward-looking vision for antiviral research is to fuse artificial intelligence with high-resolution imaging techniques, like cryo-EM or X-ray crystallography, to "de-buffer" virions — disrupting their protective stabilizers — and trigger hypersensitivity responses, where infected cells self-destruct to halt viral spread. This could expose viruses like HIV, making them more vulnerable to immunity and reducing reservoirs. Through collaborative initiatives like the COVID Moonshot, a real global effort using crowdsourced AI for non-patented antivirals, we can pioneer pan-viral cures that eradicate infections, alleviate comorbidities (e.g., hypertension in HIV), and prevent future pandemics by creating broad-spectrum therapies through understanding the replication cycle of viruses and the viral protein interaction with host factors. Grounded in my structural biology work (e.g., GDH and TREX1 studies), it emphasizes interdisciplinary innovation for equitable, transformative solutions.

As we wage this molecular war, interdisciplinary innovation, like mentoring the next generation, as I do at Meharry, will ensure victory. The pandemics of tomorrow demand we act today.

From Awareness To Action

The battle against viruses isn't just for scientists — it's a global team effort. Start by spreading the word. Follow updates from organizations like the INTREPID Alliance. Support funding for biochemistry, molecular biology, and structural biology through petitions or donations to groups like the NIH or WHO. Check out local events or volunteer for health disparities research. For aspiring scientists, dive into free tools like AlphaFold or online courses on Coursera. Together, we can build resilience. Get vaccinated, stay informed on outbreaks via apps (like the CDC's), and advocate for equitable access to treatments. Let's make the pandemics of tomorrow history.

References

1. Prakash P, Khodke P, Balasubramaniam M, Davids BO, Hollis T, Davis J, et al. Three prime repair exonuclease 1 preferentially degrades the integration-incompetent HIV-1 DNA through favorable kinetics, thermodynamic, structural, and conformational properties. J Biol Chem 2024; 300(7):107438.
2. Davids BO, Balasubramaniam M, Sapp N, Prakash P, Ingram S, Li M, et al. Human Three Prime Repair Exonuclease 1 Promotes HIV-1 Integration by Preferentially Degrading Unprocessed Viral DNA. J Virol 2021; 95(17):e0055521.
3. Prakash P, Swami Vetha BS, Chakraborty R, Wenegieme TY, Masenga SK, Muthian G, et al. HIV-Associated Hypertension: Risks, Mechanisms, and Knowledge Gaps. Circ Res 2024; 134(11):e150-e175.
4. Morling KL, ElGhazaly M, Milne RSB, Towers GJ. HIV capsids: orchestrators of innate immune evasion, pathogenesis and pandemicity. J Gen Virol 2025; 106(1).
5. Bogdanow B, Mühlberg L, Gruska I, Vetter B, Ruta J, Elofsson A, et al. Structural host-virus interactome profiling of intact infected cells. Nat Commun 2025; 16(1):6713.
6. De Clercq E, Zhang Y, Li G, Deng Y, Khouri R, Růžek D, et al. Lenacapavir: A capsid inhibitor for HIV-1 treatment and prevention. Biochem Pharmacol 2025; 240:117125.
7. Global, regional, and national burden of HIV/AIDS, 1990-2021, and forecasts to 2050, for 204 countries and territories: the Global Burden of Disease Study 2021. Lancet HIV 2024; 11(12):e807-e822.
8. Global, Regional, and National Burden of Cardiovascular Diseases and Risk Factors in 204 Countries and Territories, 1990-2023. J Am Coll Cardiol 2025; 86(22):2167-2243.
9. Mehnaz S, Anjum R, Mithila FR, Dewan SMR, Islam MR. The Current Pathogenicity and Potential Risk Assessment of Nipah Virus as Potential Cause of "Disease X": A Narrative Review. Health Sci Rep 2024; 7(12):e70241.
10. Ropón-Palacios G, Silva JP, Gervacio-Villarreal EA, Galarza JPR, Zuta MC, Otazu K, et al. Integrated computational biophysics approach for drug discovery against Nipah virus. Biochem Biophys Res Commun 2025; 745:151140.
11. Prakash P, Punekar NS, Bhaumik P. Structural basis for the catalytic mechanism and α-ketoglutarate cooperativity of glutamate dehydrogenase. J Biol Chem 2018; 293(17):6241-6258.
12. Yuan JX, Hao Y, Dai XZ, Hong JJ, Chen CY, Huo ZX, et al. Literature review of advances and challenges in KRAS G12C mutant non-small cell lung cancer. Transl Lung Cancer Res 2025; 14(7):2799-2820.
13. Zhu JD, Meng W, Wang XJ, Wang HC. Broad-spectrum antiviral agents. Front Microbiol 2015; 6:517.
14. Yuan M, Zheng Y, Wang F, Bai N, Zhang H, Bian Y, et al. Discussion on the optimization of personalized medication using information systems based on pharmacogenomics: an example using colorectal cancer. Front Pharmacol 2024; 15:1516469.
15. Chen C, Wang J, Pan D, Wang X, Xu Y, Yan J, et al. Applications of multi-omics analysis in human diseases. MedComm (2020) 2023; 4(4):e315.
16. Zhou G, Rusnac DV, Park H, Canzani D, Nguyen HM, Stewart L, et al. An artificial intelligence accelerated virtual screening platform for drug discovery. Nat Commun 2024; 15(1):7761.
17. Matinvafa MA, Makani S, Parsasharif N, Zahed MA, Movahed E, Ghiasvand S. CRISPR-Cas technology secures sustainability through its applications: a review in green biotechnology. 3 Biotech 2023; 13(11):383.

About The Author

Prem Prakash, Ph.D., serves as a senior research scientist at Meharry Medical College's Center for AIDS Health Disparities Research, where he leverages his expertise in protein X-ray crystallography, enzymology, and HIV-1 drug design. He received a BS in chemistry, biochemistry, and microbiology from Presidency College in Bangalore, India. He then pursued an MS in biotechnology, specializing in biochemistry and biophysics, at the Indian Institute of Technology Bombay, followed by a Ph.D. in structural biology and enzymology from the same institution.

Since August 2020, he has been at the Center for AIDS Health Disparities Research, Meharry Medical College. Prior to that, while at the Department of Green Center for Reproductive Biology, UT Southwestern Medical Center, he honed skills in purifying proteins from insect cells and preparing cryoEM grids for structural analyses of large human protein complexes.

Reach out to me on LinkedIn or through email.