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Metalloproteinase imbalance in HIV-1: Subtype comparison in CSF and serum
Sérgio Monteiro De Almeida1, Indianara Rotta1, Antony Liao2
1Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
Abstract:
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.
Insights
Central nervous system (CNS) inflammation in people with HIV (PWH) is linked to higher metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in cerebrospinal fluid (CSF). However, HIV-1C strains did not show differences compared to HIV-1B strains.
Area of Science:
- Neuroimmunology
- Virology
- Biochemistry
Background:
- Persistent inflammation in the central nervous system (CNS) of people with HIV (PWH), despite antiretroviral therapy (ART), is driven by ongoing HIV replication.
- This inflammation contributes to neuronal damage and is associated with specific HIV-1 subtypes and viral proteins.
- Metalloproteinases (MMPs) and their inhibitors (TIMPs) are key regulators of extracellular matrix remodeling and inflammation, potentially playing a role in HIV-associated neuroinflammation.
Purpose of the Study:
- To compare levels of MMPs and TIMPs in the cerebrospinal fluid (CSF) and serum of people with HIV (PWH) versus people without HIV (PWoH).
- To investigate potential differences in MMP and TIMP levels between HIV-1B and HIV-1C subtypes, hypothesizing lower levels in HIV-1C due to the C30S31 substitution in the HIV-1C Tat protein.
- To explore the correlation between CSF and serum levels of MMPs and TIMPs and assess the compartmentalization of inflammation within the CNS.
Main Methods:
- Analysis of 68 paired CSF and serum samples from PWH (HIV-1B, n=27; HIV-1C, n=26) and 19 PWoH.
- Quantification of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 using immunoassays.
- Statistical comparisons using multiple linear regression, adjusting for relevant covariates, and employing the Benjamini-Hochberg method for multiple testing correction.
Main Results:
- MMP-9, MMP-2, MMP-9/TIMP-1, and MMP-2/TIMP-2 levels were significantly higher in the CSF of PWH compared to PWoH (p < 0.001).
- No significant differences in CSF or serum MMP and TIMP levels were observed between HIV-1B and HIV-1C subtypes.
- The specific Tat protein substitution (C30S31) in HIV-1C did not influence MMP and TIMP expression.
Conclusions:
- Elevated MMPs and TIMPs in the CSF of PWH suggest a compartmentalized inflammatory response within the CNS.
- The hypothesized difference in MMP/TIMP levels based on HIV-1C Tat protein substitution was not supported by the findings.
- Further research is needed to fully elucidate the role of specific viral factors in HIV-associated neuroinflammation and neuronal damage.
