Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy

Despite prolonged treatment with highly active antiretroviral therapy (HAAR T), infectious HIV-1 continues to replicate and to reside latently in resti ng memory CD4(+) T lymphocytes, creating a major obstacle to HIV-1 eradicat ion It is therefore not surprising to observe a prompt viral rebound after discontinuation of HAART. The nature of the rebounding virus, however, rema ins undefined. We now report on the genetic characterization of rebounding viruses in eight patients in whom plasma viremia was undetectable throughou t about 3 years of HAART. Taking advantage of the extensive length polymorp hism in HIV-1 env, we found that in five patients who did not show HIV-1 re plication during treatment, the rebound virus was identical to those isolat ed from the latent reservoir. In three other patients, two of whom had been free of plasma viremia but had showed some residual viral replication, the rebound virus was genetically different from the latent reservoir virus, c orresponding instead to minor viral variants detected during the course of treatment in lymphoid tissues. We conclude that in cases with apparent comp lete HIV-1 suppression by HAART, viral rebound after cessation of therapy c ould have originated from the activation of virus from the latent reservoir . In patients with incomplete suppression by chemotherapy, however, the vir al rebound is likely triggered by ongoing, low-level replication of HIV-1, perhaps occurring in lymphoid tissues.