Previous studies have shown that IL-7 or IL-2+IL-7 stimulation is able to induce HIV-1 reactivation in latently infected, resting cells isolated from infected individuals 
and in thymocytes from a SCID-hu mouse model of HIV-1 latency 
. However, the above studies did not analyze the effect of homeostatic proliferation on the size of the latent reservoir in TCM
. In the present study, we show that, although homeostatic proliferation signals are able to induce partial viral reactivation from HIV-1 latency in TCM
cells, cell proliferation may nullify the potential benefits of IL-7 as a natural “anti-latency” treatment. It is noteworthy that while incubation with IL-2 alone induced very low levels of reactivation in our system, others have reported significant effects of IL-2 
. Two crucial differences come to mind when trying to reconcile our study with that of Gondois-Rey et al. 
. First, Gondois-Rey et al. used PHA instead of αCD3/αCD28 for T-cell stimulation. Second, our studies isolate cells with a pure central memory phenotype, whereas Gondois-Rey et al. did not discriminate between central, transitional and effector memory cells. These discrepancies may underlie dramatic differences in the responsiveness of various T cell subsets to IL-2 and should be further examined.
Because HIV-1 latently infected TCM
cells do not detectably express viral antigens, there is no reason to suspect that homeostatic proliferation will occur at a different rate in infected versus uninfected cells. In fact, our results using cultured TCM
indicate that there is not a statistically significant difference between latently infected cells and uninfected ones () in their abilities to proliferate. We surmise that the normal ability of latently infected cells to proliferate is an important contributor toward their long-term maintenance. This result also indicates that the resting state is not an absolute requirement toward establishing latency. A clear precedent for this notion is the well known fact that certain immortalized cell lines can harbor latent viruses indefinitely, which are capable of being reactivated 
. Therefore, cell division status can be independent of latency, and we here extended this notion to primary TCM
Using cultured TCM cells, we were also able to model the dramatic effect of antigenic stimulation on the size of the latent reservoir in TCM. The results indicate that antigenic stimulation can deplete the latent reservoir via viral reactivation, whereas weak stimuli, such as IL-2 or IL-2+IL-7, are unable to do so ().
In this report, we carefully analyze the effect of homeostatic proliferation and antigen stimulation on HIV-1 latently infected TCM in vitro. As this reservoir in vivo is extremely long-lived and impervious to conventional anti-retroviral treatment, analysis of other factors that may impact the latent reservoir in patients is extremely compelling. Such factors will likely include a plethora of immunological mediators, general and specific inflammatory conditions, and the presence of other infectious agents.
In addition to the documented ability of IL-7 to induce reactivation of latent HIV-1 in resting cells from patients 
, recombinant IL-7 (rIL-7) has shown efficacy in combating lymphopenia when administered to HIV-1 patients 
. These benefits, combined with the low toxicity observed in the setting of rIL-7 administration, have prompted several clinical trials with the goal of eradicating the HIV-1 reservoir with rIL-7 administration. In the past, potential anti-latency drugs were evaluated for their ability to induce virus replication in the face of minimal cellular activation 
. Given the results presented here, we propose that potential “anti-latency” drugs should also be examined for the undesired ability to induce cellular proliferation in the presence of incomplete viral reactivation.