Dynamics of the Blood Plasma Proteome During Hyperacute HIV-1 Infection

In our recent study in Nature Communications, we employed cutting-edge proteomics to explore changes in blood plasma proteins during early HIV-1 infection. The results advance our understanding of early host responses and highlight mechanisms that influence viral control and disease progression.

The Questions We Asked

HIV-1 continues to challenge global health, especially in sub-Saharan Africa where it remains a leading cause of illness. A critical but underexplored aspect of HIV-1 infection is the hyperacute phase, the so-called hyperacute HIV-1 infection (hAHI) -  a short but decisive window following infection that can shape the course of the disease. HIV-1 infection triggers complex interactions between the virus and host, beginning even before symptoms manifest. Moreover, the hAHI phase is marked by a "storm" of inflammatory responses and immune activation, a rapid surge in viral particles and immune activation, often accompanied by symptoms of acute retroviral syndrome (ARS)^1-5. Yet, while inflammatory markers have been studied, the broader proteomic changes during this critical window have been underexplored.

Our central questions were:

1. How does the plasma proteome change during hAHI?
2. Can we identify specific protein patterns linked to ARS, viral control, or rapid disease progression?
3. What can these findings reveal about the mechanisms underlying immune responses and disease outcomes?

What We Did

To answer these questions, we analyzed 157 blood plasma samples collected from 54 participants across sub-Saharan Africa. These participants represented diverse demographics and were part of two distinct cohorts: the International AIDS Vaccine Initiative (IAVI) cohort and the Durban cohort^6-9.

Samples were collected at three key time points:

• Before infection (baseline)
• During the hyperacute phase (approximately 10 days post-infection)
• At a later stage of hyperacute infection (around 30 days post-infection)

Using data-independent acquisition mass spectrometry (DIA-MS), we quantified 1,293 proteins, capturing changes in their expression levels over time. This approach allowed us to map individual dynamic proteomic changes and correlate them with clinical outcomes such as ARS symptoms, viral load, and CD4+ T-cell counts.

Key Findings

1. Diverse Protein Expression Patterns

We identified six distinct longitudinal expression profiles, representing different trajectories of protein changes during hAHI. These profiles included:

• Proteins that surged during early infection and returned to baseline.
• Proteins that decreased sharply and remained low.
• Proteins that showed persistent elevation or reduction throughout the study period.

These patterns reflect a complex interplay of immune activation, tissue damage, and viral-host interactions.

2. Biomarkers of ARS and Immune Activation

Participants with ARS, a flu-like syndrome often accompanying hAHI, exhibited specific proteomic signatures:

• Elevated levels of LILRA3, a protein involved in immune regulation, were associated with ARS.
• Decreased levels of ZYX and SCGB1A1, which modulate inflammatory and immune responses, were observed in ARS cases.

These findings suggest that these proteins could serve as early biomarkers for identifying individuals experiencing ARS.

3. Proteins Linked to Viral Control

Participants who achieved better viral control (lower viral loads without antiretroviral therapy) showed distinct protein patterns:

• Increased levels of NAPA and RAN, proteins involved in cellular transport and viral assembly, were observed in controllers.
• Lower levels of ITIH4, an acute-phase protein associated with inflammation, were also linked to improved viral control.

These proteins highlight potential mechanisms by which the host may regulate viral replication and maintain immune homeostasis.

4. Predictors of Disease Progression

Rapid CD4+ T-cell decline, a hallmark of faster HIV progression, was associated with specific proteomic changes:

• Elevated levels of Hepsin (HPN) and PRKCB, proteins involved in immune signaling and cytoskeletal dynamics, correlated with faster progression.
• Conversely, participants with slower progression exhibited lower levels of these proteins, suggesting their potential as therapeutic targets.

5. Stormers and Slumpers

Interestingly, while some proteins surged dramatically during hAHI ("stormers"), others decreased significantly ("slumpers"). This dual dynamic offers new insights into the complex regulation of immune responses during early HIV infection.

Why It Matters

These findings not only improve our understanding of early HIV-1 infection but also provide potential diagnostic and therapeutic targets. For instance, biomarkers like ZYX and SCGB1A1 could aid early detection of ARS, and proteins linked to viral control could inform future vaccine strategies.

The Journey Behind the Research

This study was possible thanks to a large team of collaborators spanning five countries and multiple disciplines. It was a rewarding journey that required meticulous work, from proteomics analysis to overcoming cohort and methodological challenges. The scale and precision of this study stand as a testament to the power of international collaboration.

Looking Ahead

While our study provides valuable insights, it also raises new questions. For example, what drives the "slumping" of certain proteins during hAHI? Could these proteins hold the key to understanding immune exhaustion or viral evasion strategies? Future research will focus on validating our findings in larger, more diverse cohorts and investigating the functional roles of key proteins. Additionally, integrating our proteomic data with other omics approaches, such as transcriptomics and metabolomics, could provide a more comprehensive view of host-virus interactions.

Acknowledgments

This work would not have been possible without the dedication of our collaborators, funders, and study participants. A heartfelt thank you to everyone involved in this journey, particularly the International AIDS Vaccine Initiative (IAVI), the Durban cohort teams, and my co-authors for their hard work and commitment.

Closing Thoughts

The dynamics of the blood plasma proteome during hAHI offer a window into the early events that shape HIV-1 pathogenesis. By illuminating these processes, we hope to contribute to the global effort to combat HIV and improve the lives of those affected by HIV-1.

Read the full paper here: https://doi.org/10.1038/s41467-024-54848-0.

References

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