Genetic Characterization of the Rebounding HIV-1 after Cessation of HAART
L. Zhang, C. Chung, B. Hu, T. He, Y. Guo, X. Jin, A. Hurley, M. Markowitz and D. D. Ho.
Aaron Diamond AIDS Research Center, The Rockefeller University, New York.
After discontinuation of HAART, almost all patients exhibit prompt viral rebound with doubling times of 1.5-2.5 days. To determine the source of the rebound virus, we conducted an extensive study to understand its genetic relationship to viruses found at primary infection, as well as to those in lymphoid tissues and the latent reservoir during treatment. We developed a new, easy technique to determine the genetic relatedness of viruses based on the known extensive length polymorphism in V1, V2, V4 and V5 regions of env. A total of 65 sequential plasma samples, along with viral sequences from tissue biopsies and latent reservoirs were studied from 4 acutely infected patients before, during, and after HAART. Despite complete suppression of plasma viremia for 3 years, replication-competent HIV-1 was successfully isolated from resting memory CD4 cells in each case. After cessation of therapy, all 4 patients had viral rebound. In 2 patients who did not have genetic evidence of residual HIV-1replication during treatment, the rebound virus was identical in length to those within the latent reservoir and at primary infection. In two patients, however, the rebound virus was dramatically different from the latent reservoir virus, and further studies showed evidence of persistent, low-level viral replication despite sustained suppression of plasma viremia below the detection limit. The rebound virus was in fact identical to minor quasispecies detected in biopsies of a lymph node and tonsil taken during the treatment course, suggesting a possible source. Interestingly, as these two patients remained off therapy, the initial rebounding virus was gradually overtaken by a strain identical to that found in the latent reservoir and at primary infection, demonstrating its replicative advantage. Similar studies are now being conducted on additional cases to confirm our initial conclusions that (1) in the setting of complete HIV-1 suppression by HAART, the viral rebound is likely due to the activation of the virus from the latent reservoir and (2) in patients with incomplete suppression by chemotherapy, the viral spread upon cessation of treatment is probably triggered by ongoing, low-level replication of HIV-1.
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