Is the Complement System Dysregulated in Preeclampsia Comorbid with HIV Infection?

Abstract

South Africa is the epicentre of the global HIV pandemic, with 13.9% of its population infected. Preeclampsia (PE), a hypertensive disorder of pregnancy, is often comorbid with HIV infection, leading to multi-organ dysfunction and convulsions. The exact pathophysiology of preeclampsia is triggered by an altered maternal immune response or defective development of maternal tolerance to the semi-allogenic foetus via the complement system. The complement system plays a vital role in the innate immune system, generating inflammation, mediating the clearance of microbes and injured tissue materials, and a mediator of adaptive immunity. Moreover, the complement system has a dual effect, of protecting the host against HIV infection and enhancing HIV infectivity. An upregulation of regulatory proteins has been implicated as an adaptive phenomenon in response to elevated complement-mediated cell lysis in HIV infection, further aggravated by preeclamptic complement activation. In light of the high prevalence of HIV infection and preeclampsia in South Africa, this review discusses the association of complement proteins and their role in the synergy of HIV infection and preeclampsia in South Africa. It aims to identify women at elevated risk, leading to early diagnosis and better management with targeted drug therapy, thereby improving the understanding of immunological dysregulation.

Keywords: HIV; complement; immunity; innate; preeclampsia; pregnancy.

Figure 1

Schematic diagram showing the activation of the complement cascade. There are three pathways via which complement is activated: CP, LP, and AP. The AP is activated when C3 spontaneously hydrolyses at low concentrations to create C3(H2O), the LP is activated when ficolin or MBL attaches to carbohydrate moieties on pathogen surfaces, and the CP is triggered by antibody attachment to cell surfaces that expose a C1q binding site. All three routes combine to generate a C3 convertase, which then cleaves C3a and C3b to cause opsonization, inflammation, and the MAC, promoting cell lysis.

Figure 2

Schematic diagram showing key complement regulators and their targets in the complement system.

Figure 3

Schematic diagram of the role of the complement system during HIV infection. It is activated by HIV-1 virus binding to gp41 and gp120. HIV-specific antibodies also contribute to complement activation. HIV-1 uses the regulatory proteins to evade complement-mediated lysis.

Figure 4

Schematic diagram showing the overview of the main effectors and regulators of the complement system during pregnancy. The primary complement regulators on human placental tissue, MCP, and CD59, are responsible for preventing inappropriate complement activation.

Figure 5

Preeclampsia in early pregnancy is caused by immune activation, specifically by variables associated with angiogenesis and complement activation fragments.

Figure 6

The function of C1q in normal placentation and adverse pregnancy outcomes.

Figure 7

Complement activation by HIV, adhesion of C1q, and transmembrane protein gp41 leading to the CP being activated.

Figure 8

The complement activation LP. When MBL interacts with viral glycoproteins through glycan-associated mannose, conformational changes occur in MBL. This triggers MASP-1 and MASP-2, which cleave complement components resulting in inflammation, pathogen, and infected cell lysis, opsonization, and inflammation.

Figure 9

Schematic illustration of complement C3 and its function. All three complement pathways form C3, which is cleaved into C3a and C3b. C3a activates and recruits inflammatory cells, whilst C3b induces phagocytosis and cell membrane disruption.

Figure 10

Diagrammatic representation of C5a’s function in preeclamptic pregnancies. Unfavourable excessive complement activation accompanied by an increase in C5a release increased soluble VEGF receptor-1 (sVEGFR-1)/sFlt-1. Reduced VEGF and PIGF levels cause placental insufficiency resulting in PE in late pregnancy.

Figure 11

Schematic overview of the MAC in the synergy of HIV infection and PE. All three complement pathways form C5, which cleaves into C5a and C5b, which then forms the MAC by recruiting the other complement components (C6–C9). Thus, increasing complement activation in HIV and PE.

Figure 12

Schematic overview showing the main functions of each complement component in the duality of PE and HIV infection.