Increasing contribution of integrated forms to total HIV DNA in blood during HIV disease progression from primary infection

Abstract

Background In the current context of research on HIV reservoirs, offering new insights into the persistence of HIV DNA in infected cells, which prevents viral eradication, may aid in identifying cure strategies. This study aimed to describe the establishment of stable integrated forms among total HIV DNA during primary infection (PHI) and their dynamics during the natural history of infection. Methods Total and integrated HIV DNA were quantified in blood from 74 PHI patients and 97 recent seroconverters (<12 months following infection, “progression cohort”). The evolution of both markers over six years was modelled (mixed-effect linear models). Their predictive values for disease progression were studied (Cox models). Findings For most patients during PHI, stable integrated forms were a minority among total HIV DNA (median: 12%) and became predominant thereafter (median at AIDS stage: 100%). Both total and integrated HIV DNA increased over a six-year period. Patients from the progression cohort who reached clinical AIDS during follow-up ( n = 34) exhibited higher total and integrated HIV DNA levels at seroconversion and a higher percentage of integrated forms than did slower progressors ( n = 63) (median: 100% vs 44%). The integrated HIV DNA load was strongly associated with the risk of developing AIDS (aRR = 2.63, p = 0.002). Interpretation The profile of “rapid” or “slower” progression in the natural history of HIV infection appears to be determined early in the course of HIV infection. The strong predominance of unstable unintegrated forms in PHI may explain the great benefit of this early treatment, which induces a sharp decrease in total HIV DNA. Fund French .

Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment

“…We here observed a direct correlation between uDNA and tDNA, in line with previous reports ( 60 , 61 ). The transcription and translation of uDNA prior to integration is thought to aid productive viral infection and to result in either preintegration latency or productive infection, and might reflect recent HIV entry in a cell and a viral reservoir, at least in some circumstances ( 62 ).…”

Dynamics in HIV‐DNA levels over time in HIV controllers

“…The median baseline HIV DNA load in these non‐controller patients was much higher than for HIV controllers (1250 copies/million PBMC). With the same mathematical models, we described an increase of +0.105 log copies/million PBMCs/year for rapid progressors, who developed AIDS during follow‐up, (n = 34, 111 samples; +5332 copies/million PBMC over six years) and +0.096 log copies/million PBMCs/year for slower progressors, who did not reach the AIDS stage during the follow‐up time (n = 63, 229 samples; +4709 copies/million PBMC over six years) .…”

Initiating Antiretroviral Treatment Early in Infancy Has Long-term Benefits on the Human Immunodeficiency Virus Reservoir in Late Childhood and Adolescence

“…Integrated HIV-DNA was quantified using ultrasensitive Alu-PCR [22]. The thresholds varied according to the available cell numbers and were calculated for each assay (median 15 copies/million PBMCs, range 4-30).…”