The Basic Science Breakthroughs Reshaping Our Fight
For over four decades, HIV has challenged scientists with its uncanny ability to evade eradication. At the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), researchers unveiled startling discoveries about how HIV hides within our cells, why some rare individuals achieve remission, and how we might leverage these insights for new therapies. These advances aren't just academic curiosities—they're rewriting our playbook for controlling and potentially curing one of humanity's most persistent viral foes 1 2 .
HIV's survival hinges on its ability to enter a state of viral latency—integrating its genetic blueprint into our DNA while remaining invisible to immune detection. The 2019 conference spotlighted a cellular defense system called the HUSH complex (Human Silencing Hub) as a master regulator of this process. This discovery emerged from a sophisticated CRISPR-Cas9 screen that systematically knocked out 20,000 genes in HeLa cells 2 .
| Protein | Function | HIV Countermeasure |
|---|---|---|
| HUSH Complex | Recruits histone modifiers for silencing | Targeted by SIV Vpx/Vpr proteins |
| NP220 | Binds viral DNA, anchors silencing complex | Disappears after viral integration |
| TRIM28 | Silences retroviruses in stem cells | Overcome during viral reactivation |
The HUSH complex explains why retroviral gene therapy vectors often fail—and suggests that blocking HUSH could flush latent HIV from reservoirs. Intriguingly, simian immunodeficiency virus (SIV) produces Vpx proteins that dismantle HUSH, hinting at potential therapeutic blueprints 1 2 .
Beyond basic mechanisms, CROI 2019 electrified the audience with reports of a second HIV patient maintaining long-term remission—the "London Patient." This individual received a stem cell transplant from a donor with the CCR5-Δ32 mutation to treat Hodgkin's lymphoma, echoing the earlier "Berlin Patient" case but with critical differences 2 3 .
| Parameter | Berlin Patient | London Patient | Düsseldorf Patient |
|---|---|---|---|
| Conditioning | Full chemo + irradiation | Reduced-intensity chemo | Reduced-intensity chemo |
| Transplants | 2 | 1 | 1 |
| ART Interruption | 3 years post-transplant | 16 months post-transplant | 6 months post-transplant |
| Remission Duration | 12+ years | 18+ months (at CROI) | 3 months (at CROI) |
The London Patient case demonstrated that irradiation isn't essential for remission. Critically, declining HIV antibodies—a marker of diminishing viral antigens—suggested true remission rather than mere control. As antibody levels fell below detection in 2 of 13 ICISTEM cohort patients, this emerged as a potential biomarker for cure studies 2 3 7 .
While cure research advanced, CROI 2019 also delivered breakthroughs in preventing transmission—including a landmark trial redefining pre-exposure prophylaxis (PrEP).
This study compared two PrEP regimens in 5,387 high-risk MSM and transgender women:
| Outcome | FTC/TDF | FTC/TAF | Significance |
|---|---|---|---|
| HIV Incidence | 0.34/100 PY | 0.16/100 PY | Non-inferiority established |
| Bone Density Change | -1.0% | +0.5% | TAF better for bone health |
| Renal Biomarkers | Elevated | Stable | TAF safer for kidneys |
| Resistance Cases | 4 (FTC-R) | 0 | TAF may lower resistance risk |
Genome-wide gene function analysis. Identified HUSH complex components 2 .
Detects <1 HIV RNA/mL. Measured reservoirs in cure cases.
Quantifies replication-competent virus. Confirmed London Patient remission.
Immune cell profiling. Tracked CD4+ T cell chimerism post-transplant.
Targeting HUSH with small molecules could reactivate latent virus for elimination—an approach more precise than HDAC inhibitors like romidepsin, which failed in ACTG A5315 7 .
CCR5 gene editing (e.g., zinc finger nucleases) showed modest delays in viral rebound, hinting that combining it with immunotherapy might yield functional cures 7 .
With TAF/FTC, injectable antibodies, and on-demand inserts, prevention is becoming adaptable to diverse lifestyles.
"Treatment is the best method of ensuring long-term health—but science is narrowing the path to remission."
The molecular padlocks hiding HIV are finally being picked, bringing us closer than ever to ending the epidemic.