New Insights into HIV-1 and its Impact on the Brain: The Role of Extracellular Vesicles

Human immunodeficiency virus type-1 (HIV-1) remains a major global health issue, causing significant illness and death despite the availability of effective antiretroviral therapies that control viral replication. However, even with these treatments, the virus can hide within cells and continue to produce viral components. A recent study has revealed crucial insights into how HIV-1 persists and its potential effects on the brain.

The Hidden Viral Reservoir

In people living with HIV, the virus integrates itself into the DNA of host cells, forming what is known as a latent reservoir. This reservoir can produce viral RNA transcripts, which are pieces of genetic material that help the virus replicate and spread. Understanding the behavior of this latent reservoir is essential for developing better treatments and potentially finding a cure.

The Study: Analyzing HIV-1 in Body Fluids

Researchers at the National Institute of Neurological Disorders and Stroke, National Institutes of Health conducted a study involving 84 HIV-positive individuals, 43 of whom were observed over time. They discovered that HIV-1 RNA is present in extracellular vesicles (EVs) found in cerebrospinal fluid (CSF) and blood serum. EVs are tiny, membrane-bound particles released by cells that can carry various molecules, including RNA, between cells.

Key Findings

  1. Presence of HIV-1 RNA in EVs: The study found HIV-1 RNA in EVs from both CSF and serum in all participants. This indicates that the virus is actively producing RNA transcripts, even in the presence of antiretroviral drugs.
  2. Correlation with Neurocognitive Dysfunction: There was a notable link between the amount of EV-associated HIV-1 RNA in the CSF and neurocognitive issues in participants. This suggests that the virus may contribute to brain problems in people living with HIV.
  3. Compartmentalization of Viral Transcripts: Sequencing revealed that defective viral RNA transcripts were compartmentalized, meaning they were found in specific areas, such as the CSF and serum, in distinct patterns.

EV HIV RNA copy number is correlated with neurocognitive impairment

Fig. 3

a Spearman correlation matrix was used to visualize the relationships specifically between RNA copy numbers and clinical outcomes (n = 84). The correlation matrix uses color (blue = positive; red = negative) to depict the two-sided, pairwise Spearman correlation results (without adjustments for multiple comparisons). Significant two-sided correlations were shown, while non-significant correlations were omitted (white). Pairwise tests that were significant at the 0.05 level were further investigated graphically and in a linear model predicting clinical outcomes, first unadjusted, and then adjusted for covariates (sex, age, duration of ARV treatment, duration of HIV infection, nadir CD4, and viral load). CSF Long LTR was significantly associated with (b) overall T-score (r = −0.28, p = 0.010), (c) Executive Function (r = −0.36, p = 0.001), and (d) Attention and Working Memory (r = −0.22, p = 0.047). The gray region represents pointwise 95% confidence intervals and gray line represents the unadjusted r. CSF cerebrospinal fluid, TAR transactivation response element, LTR long terminal repeat, GDS global deficit score. Source data are provided as a Source Data file.

Implications for Understanding HIV-1

These findings highlight that previous research may have underestimated the amount of HIV present in the body, particularly in the brain. The study underscores the importance of the latent reservoir and its ongoing activity, which can lead to complications despite effective antiretroviral therapy.

The Significance for Patients

For people living with HIV, this research is crucial. It suggests that the virus’s ongoing activity, even when it seems under control, can still impact their health, especially their cognitive function. This emphasizes the need for new therapeutic strategies that target the latent reservoir more effectively.

Moving Forward

The study opens up new avenues for research and treatment:

  • Developing Therapies: Future treatments could aim to target the latent reservoir more precisely to reduce the production of viral RNA.
  • Monitoring Brain Health: Regular monitoring of neurocognitive function in people with HIV might be necessary to catch and address potential issues early.
  • Exploring EVs: Further studies on EVs could provide deeper insights into how HIV-1 spreads and persists in the body.

Conclusion

This study shines a light on the hidden activities of HIV-1 in the body and its potential impact on brain health. Understanding the role of EVs in carrying viral RNA offers a new perspective on managing and eventually overcoming the challenges posed by HIV. As researchers continue to unravel the complexities of this virus, there is hope for more effective treatments and improved quality of life for those affected by HIV.

DeMarino C, Denniss J, Cowen M, Norato G, Dietrich DK, Henderson L, Gollomp E, Snow J, Pandya D, Smith B, Nath A. (2024) HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes. Nat Commun 15(1):4391. [article]

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