HIV is released from latently infected cells about five to eight days after antiretroviral treatment interruption, according to researchers studying four cohorts. That rate -- the first directly estimated from treatment-interruption cohorts -- is much slower than previously modeled estimates, suggesting that a smaller reduction in the latent reservoir than previously assumed may ensure one year off treatment without viral reactivation.
When suppressive antiretroviral therapy stops, note researchers from the University of New South Wales (UNSW) and other centers, HIV rebounds within two to three weeks, apparently because infectious HIV is released from a reservoir of long-lived latently infected CD4+ T cells. HIV-cure strategies depend on purging that reservoir, and reducing the size of the latently infected pool may permit finite antiretroviral treatment interruptions without viral rebound.
Previous research estimated that latent cell numbers would have to be cut 2000-fold to permit an average one-year treatment-free remission. To obtain a tighter fix on how much the latent reservoir must be drained to allow one year without antiretroviral therapy, the UNSW team aimed to provide the first direct estimate of how soon HIV rebounds after treatment interruption by tracking rebounds in 100 patients from four interruption cohorts.
The researchers noted that the average delay between treatment interruption and viral detection represents the sum of two processes -- time to successful viral reactivation, and time to detection of reactivated virus. Calculated average frequency of viral reactivation proved consistent across the four treatment-interruption cohorts -- 5.1, 6.3, 7.2 and 7.6 days. Further analysis of two additional cohorts determined similar reactivation times of 5.1 days and 7.2 days.
Overall reactivation frequency in these cohorts averaged 6.0 days (confidence interval 5.5 to 6.6). This rate is about 24 times lower than previous estimates, which relied on modeling to estimate time to viral reactivation. Previous analyses suggested the latent cell reservoir would have to be slashed 2000-fold to permit one year of antiretroviral interruption without viral rebound; the new viral recrudescence estimate suggests only a 50- to 70-fold latent reservoir reduction could permit a one-year interruption without rebound.
The suggested long quiescence of latently infected cells, the authors propose, could explain lengthy periods of viral remission without treatment -- and eventual rebound -- in the Mississippi baby and after stem-cell transplantation. The researchers suggest that "understanding the mean frequency of recrudescence from latency is an important first step in approaches to prolong antiretroviral-free viral remission in HIV." They call for more work to pinpoint predictors of time to viral recrudescence "so that these measures may be used as proxies to assess the efficacy of HIV eradication interventions."
Mark Mascolini is a freelance writer focused on HIV infection.