Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The p17 protein is an important structural component of HIV, formed by the cleavage of the Gag polyprotein. Its functions include forming the viral matrix, supervising the transport of Gag to the cell membrane, and participating in viral assembly and maturation. The p17 protein influences interactions with cellular receptors, modulates lymphocyte activity, promotes proinflammatory responses, and influences B-cell proliferation and angiogenesis.

In the manuscript submitted for review, the authors provide a compelling account of how p17 contributes to endothelial activation, aberrant angiogenesis and vascular inflammation, lymphangiogenesis, prothrombotic states, tumorigenesis, systemic inflammation, and neuroinflammatory processes, even in the context of effective antiretroviral therapy. They further describe strategies to counteract the harmful biological effects of p17, proposing these approaches as potential adjuncts to antiretroviral therapy for mitigating HIV-related complications. The authors present the significant problem of the adverse activity of extracellular p17 and its variants in a comprehensive manner while also identifying important directions for future research. The article is complemented by three figures illustrating the molecular mechanisms triggered by extracellular p17, p17/vp17-induced vascular dysfunction, and the systemic pro-inflammatory and neuroinflammatory signatures associated with p17.

Author Response

Comment 1: The p17 protein is an important structural component of HIV, formed by the cleavage of the Gag polyprotein. Its functions include forming the viral matrix, supervising the transport of Gag to the cell membrane, and participating in viral assembly and maturation. The p17 protein influences interactions with cellular receptors, modulates lymphocyte activity, promotes proinflammatory responses, and influences B-cell proliferation and angiogenesis. In the manuscript submitted for review, the authors provide a compelling account of how p17 contributes to endothelial activation, aberrant angiogenesis and vascular inflammation, lymphangiogenesis, prothrombotic states, tumorigenesis, systemic inflammation, and neuroinflammatory processes, even in the context of effective antiretroviral therapy. They further describe strategies to counteract the harmful biological effects of p17, proposing these approaches as potential adjuncts to antiretroviral therapy for mitigating HIV-related complications. The authors present the significant problem of the adverse activity of extracellular p17 and its variants in a comprehensive manner while also identifying important directions for future research. The article is complemented by three figures illustrating the molecular mechanisms triggered by extracellular p17, p17/vp17-induced vascular dysfunction, and the systemic pro-inflammatory and neuroinflammatory signatures associated with p17.

Response 1: We thank Reviewer 1 for the thorough and constructive evaluation of our work. We are pleased that their analysis accurately reflects our intention to integrate current evidence on this interesting yet intricate topic.

Reviewer 2 Report

Comments and Suggestions for Authors

This review paper, titled “Beyond Viral Assembly: The Emerging Role of HIV-1 p17 in Vascular Inflammation and Endothelial Dysfunction”, provides a comprehensive overview of current knowledge on HIV-1 p17 and its variants, which drive vascular and neuroinflammatory complications in HIV infection. This paper also highlights that HIV‑1 p17 is a multifunctional viral factor with persistent extracellular secretion that drives pathology even under antiretroviral therapy (ART). In general, this is an interesting review article.

Suggestion:

Given that the p17 protein and its variants may trigger diverse biological activities, a summary table would greatly enhance reader comprehension. This table should detail the respective roles of p17, S75X, and c-terminal insertions (or other variants) in chronic immune activation, vascular dysfunction, lymph angiogenesis, pro-thrombotic states, tumorigenesis, systemic inflammation, and neuroinflammatory processes.

Author Response

Comment 1: This review paper, titled “Beyond Viral Assembly: The Emerging Role of HIV-1 p17 in Vascular Inflammation and Endothelial Dysfunction”, provides a comprehensive overview of current knowledge on HIV-1 p17 and its variants, which drive vascular and neuroinflammatory complications in HIV infection. This paper also highlights that HIV‑1 p17 is a multifunctional viral factor with persistent extracellular secretion that drives pathology even under antiretroviral therapy (ART). In general, this is an interesting review article.

Suggestion: Given that the p17 protein and its variants may trigger diverse biological activities, a summary table would greatly enhance reader comprehension. This table should detail the respective roles of p17, S75X, and c-terminal insertions (or other variants) in chronic immune activation, vascular dysfunction, lymph angiogenesis, pro-thrombotic states, tumorigenesis, systemic inflammation, and neuroinflammatory processes.

Response 1: We thank Reviewer 2 for the positive assessment of our review. We greatly appreciate the suggestion to include a summary table outlining the distinct biological activities of p17, S75X, C-terminal insertion variants, and other relevant mutants across key pathological processes. This table has now been added as Table 1 at the end of Section 4. We believe this addition strengthens the manuscript considerably, for which we are extremely grateful.