Suzuki, D. I. | bioRxiv Science

bioRxiv2026

Differential properties of gp120 from HIV-1 group M subtypes A and B

HIV-1 group M subtypes A and B differ substantially in their gp120 sequence. To determine whether these differences contribute to subtype-specific complications, particularly pulmonary arterial hypertension (PAH), rats were injected with gp120 from subtype A or B. Pulmonary artery (PA) remodeling was assessed after four weeks using hematoxylin and eosin (H&E) staining and the Vessel Morphometry Analysis tool by Autona (autona.org). Subtype A gp120 potently increased PA wall thickness and right ventricular hypertrophy. The CD4-binding region of subtype A lacks a stretch of 16 amino acids (V1 N-glycosylation site), and experiments showed stronger binding of subtype B to CD4. Subtype B gp120 contains an RGKV sequence, which resembles the RGKR sequence of the rabies virus glycoprotein G that binds to the nicotinic acetylcholine receptor (nAChR). Subtype A gp120 possesses a KDKK sequence instead. Molecular dynamics simulations indicated that both sites are surface-exposed. Although nAChR is expressed in PA cells and could potentially drive the pronounced effects of subtype A, MD simulations estimated that subtype B gp120 binds more strongly to nAChR. We also noted a single amino acid difference immediately preceding the REKR furin cleavage sequence: glutamate in subtype A versus glutamine in subtype B gp120. Simulations predicted that subtype A gp120 interacts more effectively with furin, and enzyme assays demonstrated that subtype A promotes a positive feedback loop more strongly than subtype B. Thus, HIV-1 gp120 subtype A is more potent in promoting PAH, and the mechanism may involve enhancing furin activity to elevate gp120 levels.

biochemistry↗

bioRxiv2023

gp120 envelope glycoproteins of HIV-1 Group M Subtype A and Subtype B differentially affect gene expression in human vascular endothelial cells

Cardiovascular complications are seen among human immunodeficiency virus (HIV)-positive individuals who can now survive longer due to successful antiretroviral therapies. Among them, pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased blood pressure in the lung circulation due to vasoconstriction and vascular wall remodeling, resulting in the overworking of the heart. The prevalence of PAH in the HIVpositive population is dramatically higher than that in the general population. While HIV-1 Group M Subtype B is the most prevalent subtype in western countries, the majority of HIV-1 infections in eastern Africa and former Soviet Union countries are caused by Subtype A. Research on the mechanism of vascular complications in the HIV-positive population, especially in the context of subtype differences, however, has not been rigorous. Much of the research on HIV has focused on Subtype B and information on the molecular mechanisms of Subtype A is non-existent. The lack of such knowledge results in health disparities in the development of therapeutic strategies to prevent/treat HIV complications. The present study examined the effects of HIV-1 viral fusion protein gp120 of Subtypes A and B on cultured human pulmonary artery endothelial cells by performing protein arrays. We found that the gene expression changes caused by the gp120s of Subtypes A and B are different. Specifically, Subtype A is a more potent downregulator of perostasin, matrix metalloproteinase-2 (MMP-2), and ErbB/Her3 than Subtype B, while Subtype B is more effective in downregulating monocyte chemotactic protein-2 (MCP-2/CCL8), MCP-3 (CCL7), and thymus- and activation-regulated chemokine (TARC/CCL17) proteins. This is the first report of gp120 proteins affecting host cells in an HIV subtype-specific manner, opening up the possibility that vascular complications may occur differently in HIV patients throughout the world.

cell biology↗