The primary barrier to curing HIV infection is the persistence of the virus in a latent form in long-lived resting memory CD4 T cells. The number of latently infected resting memory CD4 T cells in a typical individual on ART is estimated to be in the range of 1-60 million. An important strand of HIV cure research involves attempting to reduce the size of this persistent HIV reservoir, in hopes of delaying or—better yet—preventing viral load rebound when ART is interrupted. In order to gain insight into how feasible this might be, researchers have employed mathematical modeling to estimate how the size of the HIV reservoir relates to time to viral load rebound.
A widely cited model created Alison Hill and colleagues has suggested that reservoir reductions on the order of 5-6 logs (100,000-1 million fold) would be necessary to delay viral load rebound for 30 years or more in most individuals (an outcome that would approach a lifelong cure), while a yearlong delay would likely require a drop of at least 3 logs (1,000 fold). Last month in PLoS Pathogens, a new model was published that argues that significant delays in viral load rebound might be achieved with far more modest declines in HIV reservoir size.
The study draws on data from several different clinical trials in which ART was interrupted and time to viral load rebound assessed. A series of calculations are used to generate an estimate of how often—on average—a latently infected resting memory CD4 T cell would have to start producing virus to explain the kinetics of the rise in viral load observed after ART interruption. The math is complex and opaque to a non-mathematician, but produces a result of one successful reactivation of latent HIV every six days, considerably less frequent than a previous estimate of five times per day based on studies involving drug resistance mutations (this prior estimate is used in the Alison Hill model). A separate analysis in the new paper, using different methodology based on the genetic characteristics of rebounding HIV, arrives at a reasonably similar estimate of once every 3.6 days.
The researchers extrapolate that a yearlong delay in viral load rebound might therefore be achievable with a reduction in the HIV reservoir of 60-70 fold, a more optimistic scenario than proposed previously by Alison Hill et al. But, on the surface at least, the Hill model appears more consistent with the well-publicized cases of the Boston patients, two individuals who were reported to have experienced HIV reservoir reductions of at least 3 logs as a result of receiving stem cell transplants to treat cancers. After a carefully conducted ART interruption, viral load rebound occurred after around three months in one case and eight months in the other. The authors of the new model suggest that this apparent discrepancy might be explained by the presence of a larger, unmeasured HIV reservoir in the tissues of the Boston patients.
The Alison Hill et al PNAS paper also cites a case report by Tae-Wook Chun and colleagues describing an individual with an HIV reservoir approximately 1,500 fold lower than a typical person on ART in whom viral load rebound occurred 50 days after ART interruption. Although it would be premature to draw conclusions from so few case reports, it has to be noted that a 60-70 fold decline in the HIV reservoir doesn’t appear to have delayed viral load rebound for a year in anybody as yet. And in three examples where greater reservoir reductions appear to have occurred, viral load rebound was not delayed for a year.
The cautious interpretation would be that additional data are needed to help refine the mathematical modeling and ascertain which models most closely approximate the biological reality. An intervention (beyond stem cell transplantation, which cannot be studied on a large scale) that significantly lowered HIV reservoir levels would also allow for a more direct assessment of the impact on time to viral load rebound.
A final comment on the use of the term “remission” in this context: it’s important to note the distinction between the type remission being described in this work and the “virological remission” reported in the recent case of the teenage post-treatment controller and the similar VISCONTI cohort participants. The former involves a complete absence of HIV activity due to remaining latently infected cells staying in a non-activated resting state for the duration of the remission, and any eventual viral load rebound occurring as a result of a latently infected cell becoming activated and producing infectious virus (as best as anyone can tell with available technology, this appears to be the type of remission that occurred in the Boston patients and Mississippi baby). The latter scenario of post-treatment control of viral load is different because it involves ongoing limitation of HIV replication by immune responses; in other words, low-level HIV replication activity that is kept in check by the immune system. Current evidence implies that the former type of remission is more likely to be associated with a state of health comparable to being HIV-negative (and therefore consistent with most people’s understanding of the term remission), whereas post-treatment control might be associated with some degree of inflammation-mediated risk of disease, making it perhaps questionable as to whether the term remission should be applied.
PLoS Pathog. 2015 Jul 2;11(7):e1005000. doi: 10.1371/journal.ppat.1005000. eCollection 2015.
Pinkevych M, Cromer D, Tolstrup M, Grimm AJ, Cooper DA, Lewin SR, Søgaard OS, Rasmussen TA, Kent SJ, Kelleher AD, Davenport MP.
HIV infection can be effectively controlled by anti-retroviral therapy (ART) in most patients. However therapy must be continued for life, because interruption of ART leads to rapid recrudescence of infection from long-lived latently infected cells. A number of approaches are currently being developed to 'purge' the reservoir of latently infected cells in order to either eliminate infection completely, or significantly delay the time to viral recrudescence after therapy interruption. A fundamental question in HIV research is how frequently the virus reactivates from latency, and thus how much the reservoir might need to be reduced to produce a prolonged antiretroviral-free HIV remission. Here we provide the first direct estimates of the frequency of viral recrudescence after ART interruption, combining data from four independent cohorts of patients undergoing treatment interruption, comprising 100 patients in total. We estimate that viral replication is initiated on average once every ≈6 days (range 5.1- 7.6 days). This rate is around 24 times lower than previous thought, and is very similar across the cohorts. In addition, we analyse data on the ratios of different 'reactivation founder' viruses in a separate cohort of patients undergoing ART-interruption, and estimate the frequency of successful reactivation to be once every 3.6 days. This suggests that a reduction in the reservoir size of around 50-70-fold would be required to increase the average time-to-recrudescence to about one year, and thus achieve at least a short period of anti-retroviral free HIV remission. Our analyses suggests that time-to-recrudescence studies will need to be large in order to detect modest changes in the reservoir, and that macaque models of SIV latency may have much higher frequencies of viral recrudescence after ART interruption than seen in human HIV infection. Understanding the mean frequency of recrudescence from latency is an important first step in approaches to prolong antiretroviral-free viral remission in HIV.