suPAR AND HIV DISEASE PROGRESSION

Several independent studies of HIV infected patients have demonstrated that the blood level of suPAR is intimately associated with disease stage and a strong and independent predictor of disease progression and mortality in antiretroviral-untreated patients.

Thus, the circulating level of bulk-suPAR [12,109,116], suP AR(I-III), suP AR(II-III) and suP AR(I) [12,93] are increased in moderate/advanced antiretroviral-untreated HIV infection and increases with HIV disease progression [11,12].

The blood level of bulk-suPAR is an independent predictor of mortality in early (seroconversion) [15] and late [11-14] HIV-1 and HIV-2 [13] infection. Also, the circulating level of suP AR(I-III) and suP AR(II-III) independently predicts mortality in antiretroviral-untreated HIV infected patients [12].

Besides high suPAR level, the level of uPAR/uPA-complexes is also increased in chronic HIV infection as previously suggested [12] and later confirmed [110]. In healthy individuals, part of the circulating suPAR(I- III) is associated with other molecules (ligands) [70] and altered levels of suPAR-ligand complexes is also observed in other diseases with systemic inflammation [16,117] emphasizing that this phenomenon is not specific for HIV infection. Since uPA-cleavage mainly occurs at sites with concomitant high uPA and uPAR expression [65], the concurrent high levels of suP AR(I) [12,93] and uPAR/uPA-complexes [12,110] most likely reflect increased local uPA and/or plasmin-generation with enhanced cleavage and release of uPAR and uPAR/uPA-complexes [33,65,118]. Hypothetically, high local uPA/plasmin-generation could be attributed to both HIV [35,112] and inflammation/immune activation [8].

Based on the notion that uPA exerts a significant inhibitory effect on HIV replication in vitro [35-38], it is suggested that the negative predictive value of high bulk-suPAR levels is attributed to suPAR(I-III)-mediated competitive inhibition of uPA binding to membrane-bound uPAR(I-III), with subsequent enhanced HIV replication and disease progression [37,110].

At present, there is accumulating evidence indicating that suPAR(I-III) alone cannot account for the negative predictive value of high bulk-suPAR levels in HIV infection.

The observation that suPAR and VL correlate only weakly [11] or do not correlate [12,14,93,116] in antiretroviral-untreated HIV infection indicates that suPAR and viral replication are not intimately associated.

Also, the finding that circulating suPAR(II-III) - which is devoid of uPA binding capacity - is an independent predictor of mortality in HIV infection [12] further argues against an exclusive role of suPAR(I-III).