Why can't HAART alone eradicate HIV-1?

HAART, or highly active antiretroviral therapy, suppresses HIV replication but does not eliminate the virus from chronically infected cells like macrophages and resting memory CD4+ T-cells. As a result, HIV can rebound quickly if treatment stops. Strategies to eradicate HIV aim to induce expression of the integrated HIV genome in these latently infected cells, making them vulnerable to immune-mediated killing while antiretroviral therapy prevents new infections.

What cell lines and compounds were examined in the study regarding natural compounds and HIV-1?

The research focused on whether natural compounds could trigger HIV replication in chronically infected monocytic and lymphocytic cell lines, specifically Ul and H9+ cells. The study evaluated the cytotoxicity of compounds like CDM, NDGA, Cur, and synthetic stigmasterol analogs on both uninfected and HIV-1 chronically infected cells.

What were the effects of CDM, NDGA, and Cur on HIV-1 replication in Ul and H9+ cells?

CDM, NDGA, and Cur can activate HIV-1 replication only in latently infected promonocytic cells. In Ul cells, CDM increased p24 production by approximately sevenfold, while NDGA and Cur increased it by nearly twofold. Conversely, in H9+ cells, treatment with any of these compounds resulted in lower levels of p24 antigen. Notably, synthetic analogs 1 and 2 did not increase p24 levels in Ul cells.

How might NDGA contribute to HIV-1 replication, and what further research is needed?

NDGA increased ROS production in Ul cells, which may be linked to the increase in p24 levels. Further research is needed to fully elucidate the mechanisms by which these natural compounds induce HIV-1 replication and to assess their potential as part of a comprehensive HIV eradication strategy. Understanding the specific pathways activated by each compound could lead to targeted therapies that effectively flush out the viral reservoir without causing undue toxicity.

What are the broader implications of discovering that natural compounds can induce HIV-1 replication in latently infected cells?

The research suggests certain natural compounds, such as CDM, NDGA, and Cur, can induce viral replication in latently HIV-1-infected promonocytic cells. This aligns with findings on other compounds like Ephedrae herba and Resveratrol. The potential implications include the development of new therapeutic strategies to target and eradicate HIV reservoirs. Further investigation is needed to understand the full potential and limitations of these compounds in HIV treatment.

HIV latency reversal concept art

Unlocking HIV-1: Can Natural Compounds Wake the Sleeping Virus?

Elliot Brynn in Health & Wellness December 2025 • 4 min read.

"Exploring how naturally occurring substances might help eradicate HIV-1 by stimulating the expression of the integrated viral genome in chronically infected cells."

While highly active antiretroviral therapy (HAART) effectively suppresses human immunodeficiency virus (HIV) replication, it doesn't eliminate the virus from chronically infected cells. This means that when treatment is interrupted, the virus can rapidly rebound from these hidden reservoirs, including macrophages and resting memory CD4+ T-cells.

One promising strategy for HIV eradication involves using molecules that specifically induce the expression of the integrated HIV genome. This approach aims to make latently infected cells vulnerable to immune-mediated killing, while antiretroviral therapy prevents new infections. Cytokines like IL-2 and IL-7, and small molecules with pharmacological properties, are being explored for their ability to access viral reservoirs.

New research is exploring whether compounds such as 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), nordihydroguaiaretic acid (NDGA), curcumin (Cur), and synthetic stigmasterol analogs can trigger HIV replication in chronically infected monocytic and lymphocytic cell lines.

Natural Compounds Wake Up HIV-1 in Promonocytic Cells

The study focused on whether certain natural compounds could elicit HIV replication from Ul and H9+ cells, two chronically infected monocytic and lymphocytic cell lines. Researchers evaluated the cytotoxicity of natural compounds (CDM, NDGA, and Cur) and synthetic stigmasterol analogs 1 and 2 on uninfected and HIV-1 chronically infected cells using the Trypan blue dye exclusion method.

The results showed that H9 and H9+ cells were very sensitive to CDM compared to promonocytic cells. NDGA didn't seem to affect cell viability at concentrations up to 30 μM, while Cur showed no significant cytotoxic effect at concentrations up to 10 μM. Synthetic analog 1 had CC50 values of 10 μM for U937 and Ul monocytic cells and 8.8 μM for H9 and H9+ lymphocytic cells. Compound 2 produced 50% cytotoxicity at 10 μM for HIV-infected cells Ul and H9+ and slightly lower for noninfected cells.

CDM, NDGA, and Cur showed a dose-dependent activation of HIV-1 replication in Ul cells.
No increase in p24 levels was observed in Ul cells when synthetic analogs 1 and 2 were added.
CDM increased p24 production by approximately sevenfold.
NDGA and Cur increased p24 production by nearly twofold compared with untreated control cells.
Conversely, H9+ cells treated with any compound rendered lower levels of p24 antigen.

CDM, NDGA, and Cur were able to activate HIV-1 replication only in latently infected promonocytic cells. CDM also exerted an immunomodulatory effect on HIV-1 persistently infected promonocytic cells. NDGA increased ROS production in Ul cells, which might be linked to the increase in p24 levels.

Implications and Future Directions

The study's findings suggest that certain natural compounds can induce viral replication in latently HIV-1-infected promonocytic cells. This aligns with research on other natural compounds, like Ephedrae herba and Resveratrol, that have shown similar effects.

The contrasting response observed in lymphocytic cells highlights the importance of cell type and the nature of chronic infection. It will require much additional work to understand the mechanisms responsible for p24 antigen induction by CDM, NDGA, and Cur.

These findings might be considered a relevant contribution to design efficient therapeutic strategies for attacking latent HIV reservoirs.