Mechanisms of HIV Persistence: new proofs for ongoing replication on HAART
The persistence of an HIV reservoir carrying replication-competent virus in patients on highly active antiretroviral therapy (HAART) has been documented in 1997. Although major advances have been made in the understanding of the nature of this reservoir and the mechanisms allowing its persistence, much remains to be known. For many years, it has been suggested that ongoing HIV replication persists in some patients despite undetectable plasma viremia. However, most intensification trials have challenged this hypothesis, showing no effect on low levels of HIV RNA in plasma, below 50 copies/ml. Results of a randomized, double-blinded and placebo-controlled trial show that ongoing viral replication persists, in particular in patients on a Protease Inhibitor-based regimen.
The possibility of ongoing HIV replication on HAART has been supported by several observations (1):
-presence of excess unintegrated HIV DNA in resting CD4+ T cells;
-cross-infection between resting and activated CD4+ T cells;
-higher HIV burden in lymphoid tissues than in blood;
-cell-to-cell transmission of HIV.
In recent years, however, several intensification trials have been conducted and failed to demonstrate any effect on residual viremia, between 1 and 49 copies/ml.
Only one study, from Buzon et al (2), showed a transient increase in 2-LTR circles in around 30 percent of patients on HAART receiving Raltegravir as intensification therapy.
The new study reported by Hatano et al in the Journal of infectious Diseases (3) confirms these findings with the design of a double-blind, placebo-controlled trial.
Thirty-one patients on HAART with plasma viremia <40 copies/ml for at least 1 year on HAART and more than 350 CD4 cells/mm3 received either raltegravir, 400 mg BID, or placebo, for 24 weeks.
Fifteen of these 31 patients were on a PI-based regimen (48%).
Raltegravir intensification did not have a significant effect on:
-residual plasma HIV RNA;
-cell-associated HIV RNA;
-proviral HIV DNA level;
-markers of CD4 or CD8 activation.
However, using digital droplet PCR allowing the detection of 2-LTR circles at a frequency of 0.7 per million cells, the raltegravir group showed a significant increase in the levels of these 2-LTR compared to the placebo group:
-the week 1 to 0 ratio was 8.8 fold higher
-the week 2 to 0 ratio was 5.7 fold higher.
The rise in the level of 2-LTR circles in the Raltegravir group was more pronounced in patients on PIs than in others.
In addition, a significant decrease in D-dimer levels was observed in the Raltegravir group compared to the placebo group, showing that persistent ongoing viral replication might have consequences, in particular regarding coagulation status.
1-Chun TW, Fauci AS. Viral Persistence in HIV Infection: Much Known, Much to Learn. J Infect Dis 2013; 208: 1356-8
2-Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics affected by raltegravir intensification of HARRT-suppressed subjects. Nat Med 2010; 16: 460-5
3-Hatano H, Strain MC, Scherzer R, et al. Increase in 2-Long Terminal Repeat Circles and decrease in D-dimer After raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial. J Infect Dis 2013; 208: 1436-42
Key words: HIV persistence, HIV replication, HIV reservoirs