Table 2 Effect of PCSK9 in viral infection

HCV

Treatment with PCSK9 inhibitors has been shown to reduce LDL-C by inhibiting LDLR, to have an antiviral effect on HCV infection by decreasing the surface expression of LDLR and CD81 on hepatic cells.

[47]

COVID-19

Existing human investigations have demonstrated that PCSK9 inhibitors and statins are beneficial in treating sepsis and pneumonia. These medications have the potential to function as immunomodulators against severe complications of COVID-19, including cytokine release syndrome and acute respiratory distress syndrome.

[50]

COVID-19

Patients who were randomly assigned to receive the PCSK9 inhibitor had lower rates of death and needed to be tubed within 30 days compared to those who received the placebo. Patients whose IL-6 levels were higher than the norm at the start of the study had a lower chance of dying when PCSK9 suppression was used instead of a dummy. In severe COVID-19, PCSK9 inhibition decreased IL-6 levels and was the primary endpoint of mortality or intubation need, as compared to placebo.

[51]

SARS-CoV-2

In contrast to the canonical target of PCSK9, the LDLR, the PCSK9-induced degradation of ACE2 does not require the C-terminal CHRD domain. Modeling at the molecular level indicated that ACE2 binds to the Pro/Catalytic domains of mature PCSK9. Thus, SARS-CoV-2 entrance can be modulated by the cholesterol-regulating convertases PCSK9 and SKI-1 via two distinct mechanisms.

[52]

COVID-19

Patients with Gram-negative and Gram-positive infections in the non-COVID-19 SIRS/sepsis group exhibited comparable plasma PCSK9 levels to those without any discernible pathogen in their bloodstream. In conclusion, it suggested that PCSK9 may serve as a biomarker for COVID-19; however, larger cohorts are required to confirm this.

[53]

DENV

PCSK9 is an enzyme that inhibits cholesterol uptake by decreasing LDLR recycling, a process induced by DENV infection. Hence, their results indicate that PCSK9 may have an unidentified function in the pathogenesis of DENV and that inhibitors of PCSK9 may serve as an effective host-directed therapy for DENV patients.

[54]

RVFV

It is established that an increase in PCSK9 expression and a decrease in Grp94 expression results in more rapid degradation of LDLR, including Lrp. Significantly, an inverse correlation is observed between the relative levels of sgRNA targeting PCSK9 and RVFV infectivity compared to an untreated pooled cell population. This suggests that the absence of the PCSK9 gene product leads to increased levels of Lrp1 and, consequently, greater infection levels. Collectively, these observations offer additional substantiation that RVFV infection requires a pathway that regulates Lrp1 biosynthesis and surface presentation.

[59, 60]

HIV and HCV

In an adjusted analysis, Rs17111557 was found to be correlated with LDL cholesterol levels in women coinfected with HIV and HCV but not in women mono-infected with HIV. PCSK9 polymorphism may influence the pathogenesis of HIV, especially in women co-infected with HIV and HCV. One plausible mechanism by which this effect is achieved is through the modulation of cholesterol metabolism mediated by PCSK9.

[61]

HIV

Circulating PCSK9 levels are elevated in HIV-positive individuals and are associated with systemic monocyte activation markers but not coronary plaque parameters. Further investigations are warranted to ascertain the impact of PCSK9 inhibition on coronary atherosclerotic plaque burden and immune activation, as well as atherogenesis, in the context of HIV.

[64]

MPX

Patients afflicted with MPX who have hypercholesterolemia should continue to take cholesterol-lowering medications. PCSK9 inhibitors, statins, and fenofibrates may be administered in addition to standard drugs used to treat MPX as adjuvant therapy.

[62]