Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Abstract

HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4؉ T cells and with less efficient virion production ex vivo. We also found that a potent HIV-specific CD8 ؉ T cell response was present only in those HICs whose CD4 ؉ T cells produced virus ex vivo. Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8؉ T cell response to counteract efficient viral reactivation events. IMPORTANCEThere is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4 ؉ T cells in vitro were the most difficult were those with diminished CD8 ؉ T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.

Limited HIV-1 Reactivation in Resting CD4+ T cells from Aviremic Patients under Protease Inhibitors

“…Recent publications also indicate that the size of the HIV-1 reservoir measured by total cell-associated HIV-1 DNA correlates positively with the frequency of positive recovery measurements in response to various latency-reversing agents20. Additionally, the low frequency of infected cells in the HIV-1 controllers is associated with less efficient viral reactivation21. Our data are in line with these findings indicating that limited reactivation could be a consequence of lower integration events.…”

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

“…Similar results were recently reported by Kiselinova et al (11). More recently, Noel et al also reported that the low level of total HIV DNA in cells from long-term nonprogressors (LTNPs) correlated with the low efficiency of virus production after activation ex vivo (58).…”

Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2–Infected Controllers

“…Although overall, strong CD8 + T cell-mediated HIV-2 suppression is observed in HIC2 patients, some heterogeneity, as in HIC1, is observed in these patients (39,(49)(50)(51). The absent or low CD8 + T cell-mediated HIV-2 suppression in four patients may be due to several factors.…”

“…However, we have previously shown that suppressive CD8 T cell activity in HIV-1 controllers remained low in some donors even when autologous virus was used (39). Alternatively, the absence of suppressive activity may be a consequence of the stringent control of viremia, resulting in the contraction of the HIV-2-specific CD8 + T cell response to a small pool of high-quality memory cells that fall below the detection threshold of our assay (49,52,53). Moreover, we were only able to analyze the CD8 + T cell response in blood and would not be able to measure more robust responses that were active locally in patient tissues (54).…”