Suppression of human immunodeficiency virus (HIV) and improvements in health outcomes have been achieved in infected individuals receiving antiretroviral therapy (ART). Nonetheless, the vast majority will experience plasma viral rebound upon cessation of therapy, underscoring the need for developing additional therapeutic strategies that allow durable virologic remission following the interruption of ART. Analytical treatment interruption (ATI) is an essential component of future clinical trial design to determine the efficacy of immune-based therapies in suppressing and/or eradicating HIV. Here, we investigated the effect of short-term ATI on the HIV reservoir and immunologic parameters in HIV-infected individuals.
In depth immunologic and virologic analyses were conducted using clinical specimens obtained from ten HIV-infected individuals prior to ART discontinuation, during ATI, and following reinitiation of ART. The effect of ATI on the HIV reservoir was determined by measuring the level of HIV proviral DNA, cell-associated HIV RNA, and replication-competent HIV in CD4+ T cells. Characterization of intact and defective near full-length HIV proviral DNA was performed using single-genome, next-generation sequencing. Examination of immunologic parameters included longitudinal analyses of CD4+ and CD8+ T cells as well as cytokine and inflammation markers in plasma. Expression of activation and exhaustion markers was analyzed using flow cytometry.
The median duration of the ATI phase was 57 days. All study participants experienced plasma viral rebound and resumed ART. HIV burden increased significantly in the CD4+ T cells during plasma viral rebound. However, the size of the HIV reservoirs, including the frequency of CD4+ T cells carrying replication-competent virus, returned to pre-ATI levels 6 to12 months after the study subjects resumed ART. Of note, the proportions of near full-length, genome-intact, and structurally defective HIV proviral DNA sequences were similar prior to ATI and following reinitiation of ART. Furthermore, no significant differences in immunologic or activation and exhaustion parameters were found between pre-ATI and post-ATI time points.
Our data indicate that short-term ATI is not associated with permanent expansion of the persistent HIV reservoirs nor irreversible immune system abnormalities. These findings support the inclusion of ATI in future clinical trials when evaluating strategies for achieving ART-free remission.