Background
Although antiretroviral therapy (ART) effectively suppresses viral replication, HIV-1 persists as integrated proviral HIV-1 DNA within long-lived cells. This integrated HIV-1 DNA does not only underly the risk of viral rebound but also serves as the source of viral RNA transcription, even during suppressive ART. Most of these transcripts are abortive and do not yield infectious virus, yet they could still play a role in the development of non-AIDS comorbidities.
Methods
Both HIV-1 DNA levels and HIV-1 RNA levels were determined in 1893 participants from the 2000HIV study, using digital PCR based methods to quantify total and intact HIV-1 DNA levels and total HIV-1 RNA transcripts and unspliced HIV-1 RNA transcripts. Results were expressed as copies per million CD4+ T cells. Samples that did not pass quality checks were excluded from further analysis, which included multivariate regression to assess the association between comorbidities and HIV-1 DNA levels and HIV-1 RNA levels.
Results
Total HIV-1 DNA levels (n = 1854; median: 606 IQR: 253-1248) and intact HIV-1 DNA levels (n = 1427; median: 17 IQR: 4-52) significantly correlated with each other (Pearson r = 0.58). Both parameters also correlated with total HIV-1 RNA (n: 1399; median: 134 IQR: 41-390) (Pearson r = 0.68 and r=0.38 for total and intact HIV-1 DNA respectively) and unspliced HIV-1 RNA (n: 1160; median: 26 IQR: 9-81) (Pearson r = 0.57 and 0.38 for total and intact HIV-1 DNA respectively). Older age, male sex and low CD4 nadir, which all impact the development of comorbidities, resulted in higher HIV-1 DNA and RNA levels. After correcting for these factors, higher total HIV-1 DNA levels were associated with higher odds of cardiovascular disease (CVD) developed after ART initiation (OR 1.7; 95% CI 1.4–2.1), liver fibrosis (OR 1.3 95%CI 1.1-1.7) and presence of carotid plaques (OR 1.6; 95% CI 1.2–2.2). During 2-year study follow-up, higher total HIV-1 DNA levels associated with new diagnoses of malignancy (OR 1.5; 95% CI 1.1–2.2) (Figure 1A) while total HIV-1 RNA levels were associated with CVD (OR 1.17; 95% CI 1.04-1.32) and liver fibrosis (OR 1.12, 95%CI 1.004-1.25) (Figure 1B).
Conclusions
In conclusion, the total HIV reservoir size is a key determinant in long-term health outcomes in people with HIV-1 using successful antiretroviral therapy. Larger reservoirs are linked to greater comorbidity risk, emphasizing the clinical relevance of reservoir measurement and the need for strategies that actively reduce this reservoir.
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