Introduction HIV controllers (HIC) maintain viraemia at low levels without antiretroviral treatment and have small HIV reservoirs. Nevertheless, they are heterogeneous regarding their risk of infection progression. The study of reservoirs can help elucidate this control. This study aimed to explore the factors implicated in the pathogenesis of HIV infection that are potentially associated with HIV reservoirs and their dynamics in HIC.MethodsIndividuals living with HIV included in the ANRS‐CODEX cohort with at least two HIV‐DNA measurements between 2009 and 2016 were selected. The total HIV‐DNA levels had been quantified prospectively from blood samples. Mixed‐effect linear models estimated the HIV‐DNA dynamics over time.ResultsThe median (interquartile range (IQR)) HIV‐DNA level was 1.5 (1.3 to 1.9) log copies/million peripheral blood mononuclear cells at inclusion (n = 202 individuals). These low levels showed heterogeneity among HIC. Lower levels were then associated with the protective HLA‐B*27/B*57 alleles and/or lower HIV‐RNA level at inclusion, negative hepatitis C virus serology, lower HIV‐suppressive capacity of specific CD8 T cells and lower levels of immune activation and inflammation. Interestingly, mathematical modelling of the dynamics of HIV‐DNA over time (840 measurements) showed that the number of infected cells decreased in 46% of HIC (follow‐up: 47.6 months) and increased in 54% of HIC. A multivariate analysis indicated that HLA‐B*27/B*57 alleles, a low level of HIV‐RNA and a low level of HIV‐DNA at inclusion were markers independently associated with this decrease.ConclusionsThese results offer new insights into the mechanisms of long‐term control in HIC. In half of HIC, the decrease in HIV‐DNA level could be linked to tighter viral control and progressive loss of infected cells. These findings allow the identification of HIC with a low risk of progression who may not need treatment.

Background: High HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa. Methods: In the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality. Findings: 2019 patients were followed for 9253 patient-years (median 4.9 years). At baseline, the median CD4 count was 462/mm 3 [IQR 368À571], the median plasma HIV-1 RNA 4.7 log 10 copies/ml [IQR 4.0À5.2], and the median HIV-1 DNA 2.9 log 10 copies/million PBMC [IQR 2.5À3.3]. During follow-up, 86 participants died. In univariate analysis, the hazard ratio [HR] of death was 2.67 (95% CI, 1.68À4.22) for patients with HIV-1 DNA 3 log 10 copies/million PBMC vs. others, and 2.10 (95% CI, 1.38À3.21) for patients with HIV-1 RNA 5 log10 copies/ml vs. others. In multivariate Cox regression analysis, HIV-1 DNA levels 3 log 10 copies/million PBMC were strongly associated mortality (adjusted HR = 2.09, 95% CI 1.24À3.52, p= 0.005) while the association between baseline plasma HIV-1 RNA and mortality was not significant. Interpretation: In these African adults who started ART with high CD4 counts, HIV-1 DNA was a strong independent predictor of death. The HIV reservoir still plays a prognostic role in the early ART era.