CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 1, January – April 2024 AFRICA 57 relationship between PE and HIV infection.1 Drug interactions further complicate the synaptic interplay as antiretrovirals (ARVs) polarise the immune response as well as influence the haemodynamics.1 The paragraphs below highlight the various factors and cellular interactions, underscoring the need for further investigation describing the link between HIV and PE. Angiogenesis is the formation of new blood vessels and involves migration, differentiation and proliferation of endothelial cells through upregulation of pro-angiogenic factors.1,107 These molecules increase vascular permeability and stimulate proteolysis of extracellular matrix proteins, leading to migration and maturation of endothelial cells.1,108 Angiogenesis is dysregulated in HIV, however, interestingly, Wimalasundera et al. (2002) found a decreased rate of the development of PE in HIV patients who did not receive antiretroviral therapy compared to patients receiving treatment.19,109 Possible reasons could include immune restoration and imbalance of angiogenic factors as well as the direct impact of ARVs on angiogenesis.110 The influence of HIV on the development of PE is contradictory as both sFlt and sEng are downregulated in HIV, in contrast to what occurs in PE. Immunosuppression of HIV and immune activation of PE may impact on the equilibrium between pro- and anti-angiogenic factors, leading to the progression of PE. HIV-infected cells release transactivator of transcription (Tat) protein, which, even though it stimulates angiogenesis, alters endothelial cell morphology. The Tat protein is an angiogenic factor because of similar sequences to VEGF (arginine- and lysine-rich sequences) and therefore stimulates endothelial cell adhesion through binding to Flk and KDR, and promotes endothelial cell adhesion through binding to integrins and VEGFR-2 and KDR via its basic domain. In addition, the synergistic Tat, FGF2 effect is attributed to fibroblast growth factor 2 (FGF2), which induces the expression of integrins that aid in tat binding. In addition, HIV glycoprotein 120 (gp120) binds to heparin sulphate proteoglycans (HSPG), promoting viral infectivity and release of Tat. However, the Tat protein alters endothelial cell morphology and gene transcription through attenuation of intracellular signalling as it activates the mitogen activated protein kinase (MAPK) pathway. The Tat stimulates angiogenesis through utilisation of matrix protein p17 to activate the endothelin 1/endothelin B receptor axis, thereby activating protein kinase Akt and extracellular signal-regulated kinase (ERK) signalling pathways. Moreover, gp 120 induces apoptosis in endothelial cells.16,19,111-113 Angiogenesis and antiretroviral therapy The pro-inflammatory milieu of HIV infection resembles the immune dysregulation of PE, which could explain the prevalence of PE in HIV-positive women. Interestingly, even though ARVs alleviate the inflammatory state of HIV, a recent study on ARVs showed that both angiogenesis and lymphangiogenesis were downregulated with nucleoside reverse transcriptase inhibitors (NRTIs) through two main mechanisms. First, HIV tat and matrix protein p17 counter the beneficial effects of ARVs through impaired angiogenesis.1 Second, NRTIs cause mitochondrial dysfunction, leading to increased oxidative stress and altered intracellular signalling of endothelial cells.1,114 Protease inhibitors are anti-angiogenic. They suppress the action of fibroblast growth factor and induce functional impairment of transcription factors, namely, adaptor protein 1 (AP-1), specificity protein 1 (SP1) and nuclear factor kappa B (NF kappa B), leading to deceased expression of matrix metalloproteases (MMP) and VEGF, thereby disrupting angiogenesis.1 In addition, metabolic dysregulation associated with ARV regimens have predisposed HIV-infected persons to cardiovascular disease.1,115 Antiretroviral therapy has been shown to decrease nitric oxide, increase oxidative stress and induce endothelial dysfunction, mechanisms that resemble the underlying pathophysiology of PE.1,116 It has been shown that upon ARV administration, the incidence of PE increases, however there are conflicting reports.1 A study done by Torrani et al. (2008) demonstrated improved endothelial function following commencement of ARVs.117 Savvidou et al. (2011) demonstrated normal placental perfusion in uncomplicated pregnancies of HIV-infected women in both groups, those receiving and those not receiving ARVs.118 Conversely, a study done by Sebitloane et al. (2017) illustrated the correlation between ARVs and HDP among all women with HIV and found a greater risk of mortality due to HDP among patients who received ARVs, as opposed to those who were not on ARVs.119 Further studies are needed to illustrate the effect of ARVs on lymphangiogenesis and the duration of ARVs and risk of development of PE. Immunity, HIV and PE Natural killer (NK) cell function is altered in HIV infection as well as in PE.120 In normal pregnancy, these cells promote immune tolerance and placental development. At the maternal– foetal interface, NK cell inhibitory receptors, attenuation of vascular cell interactions and secretion of hepatocyte growth factor allow for adequate trophoblastic invasion and normal placentation.1 However, this process is disrupted in PE where there is a predominance of activating receptors of NK cells.121 In HIV infection, NK cells are downregulated, similar to in a normal pregnancy.122 With administration of ARVs, NK cells inhibit HIV replication through secretion of CC chemokines, which inhibit HIV replication through non-cytolytic mechanisms.123 Studies have shown conflicting results regarding the effect of ARVs on NK cells. A study by Valentin et al. (2002) reported higher frequency of NK after initiation of ARVs.124 A study by Fria et al. (2015) showed low NK recovery following ARV exposure compared to T-cell recovery, suggesting that viral infection of NK cells is necessary for viral persistence.123,125 With regard to PE, NK cell activation may lead to impaired trophoblastic invasion, resulting in an exaggerated immune response characteristic of PE. This suggests that T-cell activation rather than NK cell recovery may explain the development of PE in HIV. Normal pregnancy is associated with T helper 2 (Th2) polarisation of the adaptive immune system, however PE is associated with a T helper 1 (Th1) pro-inflammatory phenotype.126,127 During the progression of HIV, there is polarisation towards a Th2 phenotype, however, a Th1 response is predominant in HIV-infected pregnant women on ARVs.128 These patients are therefore at increased risk of developing PE.129 It has been reported that PE is associated with an upregulation of T helper 17 (Th17) cells.130 In contrast, these cells are downregulated with the progression of HIV infection.131 However, there is a paucity of data investigating the secretion of IL-17A
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