*4.3. Lymphangiogenesis and HIV Infection*

At the mucosal level, HIV-1 uses endothelial cell co-receptors CXCR4 and CCR5 before disseminating through lymphatic endothelial channels to the lymph nodes and, thereafter, moving into the general blood circulation. HIV infection plays a crucial role in lymphatic development; nevertheless, its functional integrity is complex and not fully understood. Three HIV-1 proteins, notably the envelope glycoprotein (gp120), transactivator of transcription (Tat), and the matrix protein (p17), may contribute to HIV-associated vascular disorders. HIV-1 gp120 induces apoptosis in endothelial cells. Tat triggers angiogenesis by using the matrix protein p17 [81] to stimulate the endothelin-1/endothelin B receptor axis [82], thereby activating the protein kinase Akt and extracellular signal-regulated kinase (ERK) signaling pathways [66,77,82,83].

The secretory protein (Slit2) and its receptor roundabout protein (Robo4) expressed on endothelial cells also serve to modulate endothelial cell permeability and, hence, have a determinant participation in the pathophysiological mechanism of lymphangiogenesis [84]. Although Slit2/Robo4 interactions are not fully elucidated, a previous study reported an inhibition of VEGF-C and a blockage of VEGFR-3 [85]. Additionally, HIV-1 gp120 leads to hyperpermeability of lymphatic cells in vitro via modulation of fibronectin expression and activation of <sup>α</sup>5β1 integrins. On the other hand, Slit2 blocks the interaction between <sup>α</sup>5β1 and Robo4, thus inhibiting lymphatic hyperpermeability [81].

This results in an imbalance of the Akt and ERK signaling pathways, which leads to dysregulation of lymphangiogenesis in PE, since it was shown that, during the pathophysiology of PE, there is decreased P13K/Akt signaling [86].

#### *4.4. Lymphangiogenesis in the Duration of HAART and the Risk of Preeclampsia*

By enhancing pro-inflammatory cytokines and chemokines, HIV-1 infection mimics PE, thereby influencing the prevalence of PE among HIV positive women. The HAART intervention improves endothelial function and decreases the inflammatory milieu of PE. However, that is not evident, as the timing and duration of the HAART is not clear in most the studies. Despite long-term use of HAART improving mortality among HIV positive patients, the morbidity (particularly vascular and metabolic in nature) is still a serious concern [87]. Two HIV-1 proteins seem to undermine the beneficial action of HAART in the restoration of endothelial cell (EC) function: HIV-1 Tat and matrix protein p17, which impair the endothelial cells. A recent study on HAART showed that angiogenesis and lymphangiogenesis are downregulated with Nucleoside reverse transcriptase inhibitors (NRTIs) by inducing mitochondrial oxidative stress and subsequently impairing receptor tyrosine kinase (RTK) signaling in EC [88], suggesting that NRTIs might trigger the development of PE.

The prevalence of PE in HIV-infected pregnancies is lower; however, upon HAART administration, the risk of PE development increases [13,89]. The association between lymphangiogenesis in the duration of HAART and the risk of PE development is unclear; hence, more research on lymphangiogenesis at the maternal and fetal interface is vital, particularly in immune transfer and ARV usage.

## **5. Highly Active Anti-Retroviral Therapy**

Protease inhibitors (PI) induce the progression of Kaposi sarcoma [90]. PIs are potent anti-angiogenic factors that block FGF action [91]. PIs deter HIV aspartyl protease and, hence, the production of HIV virions, thus promoting immune restoration. Also, glucose transporter (GLUT)-4, inhibits glucose uptake and affects the cellular proteasome by triggering p53 protein intracellular accumulation, resulting in apoptosis. Finally, the functional impairment of activator protein (AP)-1, specificity protein (SP)-1 or nuclear factor kappa b (NF-κB) transcription factors leads to a decline in MMP and VEGF expression, thereby preventing angiogenesis.

Anti-retroviral drugs regimens are associated with the development of metabolic disorders such as insulin resistance, dyslipidemia, impaired glucose tolerance, and abnormal body fat distribution, which predispose HIV-infected individuals to cardiovascular-related diseases [92]. Anti-retroviral

therapy was also shown to lead to endothelial dysfunction [93,94] and decreased nitric oxide, ultimately resulting in induced endothelial oxidative stress [95], which is similarly observed during the pathophysiology of PE [96]. It is, therefore, possible that predisposition to PE may result from endothelial dysfunction and reduced nitric oxide synthase induced by HAART exposure.

Although some studies report on the endothelial HAART-induced endothelial dysfunction, conflicting reports exist. A study done by Torriani et al. (2008) showed improved endothelial function after ARV administration [97]. Additionally, Savvidou et al. (2011) found normal placental perfusion among HIV-infected women, with uncomplicated pregnancies, receiving and not receiving HAART [98]. In contrast, a study done by Sebitloane et al. (2017) evaluating the effect of HAART on HDP showed that, among all women with HIV, a greater risk of mortality due to HDP was reported among those who received HAART compared with those who did not [99].
