HIV-1 DNA Levels in Peripheral Blood Mononuclear Cells of Patients with HIV-Related Non-Hodgkin’s Lymphoma
Human immunodeficiency virus (HIV) patients face an elevated risk of developing non-Hodgkin’s lymphoma (NHL), even in the era of antiretroviral therapy (ART). This increased risk is attributed to chronic immune activation and a higher susceptibility to oncovirus infections. However, the precise mechanisms underlying HIV-related NHL (HIV-NHL) remain unclear. It is hypothesized that HIV may directly contribute to lymphoma development through additional pathways. Despite sustained ART, HIV-DNA persists in infected cells, creating a reservoir of latent infection. Whether this reservoir plays a role in the development of HIV-NHL is not yet fully understood. This study aimed to explore the relationship between HIV-1 DNA levels in peripheral blood mononuclear cells (PBMCs), plasma inflammatory cytokine levels, and their impact on the development and prognosis of HIV-NHL.
The study was conducted at the Shanghai Public Health Clinical Center and included patients admitted between May 1, 2016, and November 30, 2020. Participants were divided into four groups based on their ART status and NHL diagnosis. The first group consisted of ART-naïve HIV-NHL patients (TN-NHL), who were diagnosed with HIV-NHL but had not started ART or received any lymphoma treatment. The second group included ART-naïve HIV patients (TN-HIV), who were diagnosed with HIV but had no evidence of NHL. The third group comprised ART-experienced HIV-NHL patients (TE-NHL), who had been on ART for at least one year, achieved undetectable HIV-RNA levels (<40 copies/mL), and had no prior lymphoma treatment or other tumors or infections. The fourth group was ART-experienced HIV patients (TE-HIV), who had also been on ART for at least one year with undetectable HIV-RNA levels and no evidence of tumors or infections. Patients with incomplete clinical data or missing blood samples were excluded. Ethical approval was obtained, and written informed consent was provided by all participants.
Laboratory measurements included CD4+ and CD8+ T-cell counts, which were determined using flow cytometry. Plasma HIV-1 RNA levels were quantified using polymerase chain reaction (PCR). Genomic DNA was extracted from PBMCs, and HIV-1 DNA levels were measured using a fluorescence-based, real-time quantitative detection kit. The assay had a quantification range of 10 to 5 × 10^6 copies per 10^6 PBMCs. Additionally, plasma levels of 10 inflammatory cytokines—interleukin (IL)-1b, interferon (IFN)-a2, IFN-g, IL-8, IL-10, IL-12 p70, IL-17a, IL-18, IL-23, and IL-33—were quantified using a multi-analyte flow assay.
Statistical analysis was performed using SPSS 24.0. Continuous variables with normal distributions were expressed as mean ± standard deviation (SD) and compared using the t-test, while skewed distributions were presented as median (interquartile range [IQR]) and compared using the Mann–Whitney U test. Categorical variables were expressed as frequencies and percentages and compared using chi-squared or Fisher’s exact tests. Spearman correlation analysis and linear regression were used to assess the relationship between HIV-1 DNA levels and inflammatory cytokines. Survival rates were evaluated using the Kaplan–Meier method, and differences were analyzed using the log-rank test. A P-value <0.05 was considered statistically significant.
The study enrolled 68 ART-naïve patients, including 39 TN-NHL patients and 29 TN-HIV patients. No significant differences were observed in gender, age, CD4+ counts, CD8+ counts, or HIV-RNA levels between these two groups. Among the 48 ART-experienced patients, 21 were TE-NHL patients and 27 were TE-HIV patients. While there were no significant differences in gender, age, or CD4+ counts between these groups, the duration of ART was longer in the TE-HIV group, and CD8+ counts were higher compared to the TE-NHL group. The primary pathological types of HIV-NHL were diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), with DLBCL accounting for 61.5% of TN-NHL cases and 66.7% of TE-NHL cases.
HIV-1 DNA levels in PBMCs were significantly different among the four groups. The median levels were 791.15, 1132.65, 228.18, and 353.49 copies per 10^6 PBMCs for the TN-NHL, TN-HIV, TE-NHL, and TE-HIV groups, respectively. ART-naïve patients had higher HIV-1 DNA levels than ART-experienced patients. However, among ART-experienced patients, HIV-1 DNA levels were lower in TE-NHL patients compared to TE-HIV patients.
The study also examined plasma inflammatory cytokine levels and their correlation with HIV-1 DNA levels. Plasma IL-18 levels were significantly higher in TE-NHL patients than in TE-HIV patients, and a negative correlation was observed between PBMC HIV-1 DNA levels and IL-18 levels. Survival analysis of 46 HIV-NHL patients who received anti-lymphoma therapy revealed that lower IFN-g levels before chemotherapy were associated with better survival outcomes.
These findings suggest that in virologically suppressed HIV patients, lower HIV-1 DNA levels in PBMCs may be associated with the development of NHL. Immune activation, as indicated by elevated IL-18 levels, appears to play a role in NHL development. Additionally, plasma IFN-g levels before chemotherapy may serve as a prognostic marker for HIV-NHL.
The study has several limitations, including a relatively small sample size and the absence of longitudinal data on the prognostic value of inflammatory cytokines. Furthermore, the analysis of inflammatory cytokine levels and prognosis was based on univariate rather than multivariate analysis.
In conclusion, this study highlights the potential role of HIV-1 DNA levels and immune activation in the development and prognosis of HIV-NHL. Lower HIV-1 DNA levels in PBMCs were observed in NHL patients compared to non-NHL patients among virologically suppressed individuals. Elevated IL-18 levels may serve as a biomarker for NHL development, while increased IFN-g levels before chemotherapy are associated with a poorer prognosis. These findings provide new insights into the pathogenesis of HIV-NHL and underscore the need for further research to elucidate the underlying mechanisms.
doi.org/10.1097/CM9.0000000000002897
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