HIV X4 Viruses as Potential Agents in the Pathophysiology of HIV‐associated Pulmonary Hypertension

Abstract

Pulmonary Hypertension (PH) is a severe disease that is more frequent in HIV+ individuals even with antiretrovirals. We do not know how HIV contributes to HIV‐PH. HIV proteins like gp120 play roles in the pathogenesis of HIV‐PH. Recently, we found that CXCR4‐utilizing HIV variants (X4) are overrepresented in patients with HIV‐PH compared to CCR5‐using HIV(R5). Hence, our objective was to determine if there is a differential impact of HIV‐X4 or R5 on pulmonary endothelial cells (EC). For this, we exposed cultured human pulmonary EC to recombinant HIV gp120 X4 or R5, and PBS (mock). We measured the activity of caspases 3/7 (a marker of apoptosis) from 4‐48 hrs. We also examined gene expression in EC exposed to gp120, by PCR array. We found increased caspase 3/7 activity in all EC at 8 hrs (initial apoptotic wave); this activity decreased to baseline at 16 hrs and increased again at 24 hrs (second apoptotic wave). Compared to X4, R5 gp120 induced slightly more apoptosis in EC at 8 hrs (p=0.20) and 48 hrs (p=0.10); however, X4‐treated EC displayed less apoptosis at 48 hrs than mock or untreated EC (p=0.06). Compared to R5, we also found 8 genes significantly overexpressed in X4‐treated cells, mainly the arachidonate 5‐lipoxygenase (ALOX5) gene (5‐fold, p=0.003). Our data support that HIV‐gp120 induces apoptosis in EC. We conclude that R5 and X4 may have a differential impact on EC and that X4 induces overexpression of ALOX5. Others have shown that ALOX5 is overexpressed in PH patients and induce pulmonary artery smooth muscle and EC proliferation. It is possible that HIV‐X4 induces apoptosis‐resistance in EC after long‐term exposure. Hence, we have uncovered HIV‐X4 viruses as potential agents in HIV‐PH.