**6. Immune Maladaptation**

#### *6.1. Natural Killer Cells in Normal versus Preeclamptic Pregnancies*

Natural killer (NK) cells are dysregulated in the presence of preeclampsia and HIV infection. In normal pregnancy, these cells promote placental development by balancing the immune response at the maternal–fetal interface [100]. The function of NK cells is controlled by inhibitory receptors [101] and activating receptors, C-type lectin receptors, and Ig-like receptors (2B4)] [102–104].

During normal pregnancy, the interaction between the maternal NK cells and fetal cells is controlled by NK cell inhibitory receptors, which prevents inadequate trophoblast invasion. However, this action is prevented in PE pregnancies since activating receptors are predominant, leading to shallow trophoblast invasion [105]. Similarly, the function of NK cells during HIV infection is downregulated or similar to NK cells in a healthy pregnancy state [106]. A study conducted by Mela and Goodier showed reduced activation peripheral NK cells of HIV-infected individuals [107].

#### *6.2. Role of HAART on NK Cells and Risk of Preeclampsia Development*

Natural killer cells play a role in controlling HIV [108] and are also reported to play a role in pregnancy complications such as miscarriage, implantation failure, and PE development [109–111]. In the duration of HAART, NK cells control HIV by secreting CC chemokines. These chemokines inhibit HIV replication via activation of non-cytolytic mechanisms [112]. Several studies reported on the influence of changes that may occur on NK cells in the duration of HAART exposure, and found conflicting results. A study by Valentin et al. (2002)reported higher frequency of NK cells after HAART initiation [113]. Similar findings were shown by Ballan et al. (2007) and Michaelsson et al. (2008) [114,115]. In contrast, a study done by Fria et al. (2015) examining the HAART effect on T-cell recovery versus NK cells found low NK subset recovery after HAART exposure when compared with T-cell recovery during the early months of therapy [116], suggesting that HIV infection of NK cells is important for viral persistence [113].

NK cells are also implicated in pregnancy complications; it was documented that NK cell activation may lead to inadequate trophoblast invasion and may result in exaggerative immune response, which is commonly associated with PE development [117]. Therefore, the possible mechanism responsible for PE development in HIV-infected women might be due to T-cell activation rather than NK cell subset recovery. More studies are needed to confirm how NK cells are regulated in the duration of HAART in order to understand the pathogenesis of PE in HIV-associated pregnancies.

#### **7. Cytokines in Normal Pregnancy, Preeclampsia, HIV Infection, and in the Duration of HAART**

#### *7.1. T Helper Cell 1 and T Helper Cell 2 (Th1 and Th2)*

During normal pregnancy, anti-inflammatory (Th2) cytokines are predominant [118], whereas, during the pathogenesis of PE, pro-inflammatory (Th1) cytokines are predominant [119]. However, during the progression of HIV infection, Th2 cytokines are predominant (Figure 1) [120,121]. HIV-infected pregnan<sup>t</sup> women on HAART present a shift toward Th1 immune response [122]. Therefore, HIV-infected pregnan<sup>t</sup> women on HAART have increased risk of developing PE [123].

**Figure 1.** Schematic diagram representing how pro-inflammatory (Th1) and anti-inflammatory (Th2) cytokine are regulated in **A** non-pregnan<sup>t</sup> or HIV-uninfected, **B** normotensive or HIV-infected untreated and **C** pre-eclamptic or HIV-infected on HAART. **A** Shows a balance in the distribution of Th1 and Th2. In **B** there is an imbalance of cytokines with more Th2 release than Th1. This imbalance increases of HIV infection in untreated women. In **C** Th1 levels are higher than Th2. HAART induces Th1 response and leads to pre-eclampsia development [123].

#### *7.2. T Helper Cell 17 (Th17) and T Regulatory Cells (Treg)*

Immune cells involved in pregnancy extend from Th1/Th2 into the Th1/Th2/Th17 and regulatory T cells (Treg), introducing Treg as regulators of Th17 lymphocytes and other immune cell types involved in placental development and maintenance [118,124].

Th17 cells are characterized by the secretion of IL-17/IL-17A and are also associated with inducing Th1 cytokine production. An upregulation of Th17 cells is associated with the pathophysiology of autoimmune, chronic inflammatory diseases, allergic disorders, and graft-rejection reactions [125]. Furthermore, it was reported that Th17 cells are upregulated in PE compared to normotensive pregnancies [126,127] and downregulated during the progression of HIV infection [128]. Currently, no studies investigated how IL-17A is regulated in the presence of both PE and HIV infection; more studies are needed in order to have a better understanding of how this cytokine is regulated in the pathophysiology of both conditions, especially in the duration of HAART.

Regulatory T cells are another type of lymphocytes involved in the pathophysiology of PE. In pregnancy, upregulation of these cells is important for maintaining normal pregnancy development [129–131]. Downregulation of Treg cells was reported in PE [132].

In the presence of HIV infection, the frequency of Treg cells is increased, implying their role in the progression of the disease [133–135]. In the duration of HAART, the frequency of Treg cells was shown to be decreased or similar to that of HIV-uninfected individuals [136,137]. Currently, there are no studies that investigated how Treg cells are regulated in the presence of both PE and HIV infection. Therefore, more studies are needed in order to improve managemen<sup>t</sup> of PE in the presence of HIV infection, and in order to have a better understanding of the pathophysiology of PE in the presence of HIV infection.
