Metalloproteinase imbalance in HIV-1: Subtype comparison in CSF and serum

Persistent central nervous system (CNS) inflammation, driven by ongoing HIV replication in the CNS reservoir despite antiretroviral therapy (ART), contributes to neuronal damage. We hypothesized that levels of metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) would be higher in the cerebrospinal fluid (CSF) of people with HIV (PWH) than in people without HIV (PWoH), but lower in HIV-1C than HIV-1B, due to C30S31 substitution on the HIV-1C Tat protein. The objectives were to compare MMP and TIMP levels in PWH versus PWoH and HIV-1C versus HIV-1B. Sixty-eight paired CSF and serum samples from PWH (HIV-1B, n = 27; HIV-1C, n = 26) and 19 PWoH were analyzed. MMP-2, -3, -9, and TIMP-1, -2 were quantified using immunoassays, compared using multiple linear regression, adjusting for age in PWH versus PWoH, and plasma HIV RNA suppression and nadir CD4 in HIV-1B versus C or Tat variants. The Benjamini-Hochberg (BH) method was used for multiple testing correction, and the Spearman method (ρ) for correlation. MMP-9, MMP-2, MMP-9/TIMP-1, and MMP-2/TIMP-2 in CSF were higher in PWH than PWoH (Cohen's d [95% CI] for each: 1.57[0.98,2.16], 1.19[0.62,1.76], 1.82[1.22,2.43], 1.15[0.58,1.72], all p < 0.001). CSF and serum MMPs and TIMPs were comparable in HIV-1B versus C, and Tat C30C31 versus C30S31 (p > 0.05). MMP-9, MMP-2, and TIMP ratios are higher in CSF, but not in serum, and the weak positive correlation between CSF and serum MMP-3 and TIMP-1 supports a compartmentalized inflammatory response in the CNS. The HIV-1C Tat substitution (C30S31) did not interfere with MMPs and TIMPs expression in CSF or serum.