Latently infected resting CD4 T cells: A barrier to HIV -1 eradication

• Main Author: Finzi, Diana
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2000
• Subjects: Immunology
• ISBN: 0599683562; 9780599683563

Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) results in a dramatic decrease in plasma viral load to undetectable levels. Prolonged suppression of active viral replication led to the first rational predictions for virus eradication in treated individuals provided there were no other viral reservoirs or sanctuary sites. One potentially stable reservoir for HIV-1 is comprised of latent provirus in a small frequency of resting CD4+ T cells. Although latently infected CD4 + T cells do not produce virus, these cells may become fully competent for active production of progeny virus if the appropriate conditions arise. The lifespan of resting CD4+ T cells with latent virus and whether these cells persist in patients treated with combination therapy was not known. In this thesis we examine the hypothesis that a reservoir of proviral HIV-1 DNA persists in resting CD4+ T cells of patients on combination therapy and may prevent virus eradication. We conducted a cross-sectional study that identified resting CD4 + T cell populations of extremely high purity as a reservoir for proviral replication-competent virus in patients on currently recommended HAART regimens. We used a virus culture assay to show that in a study of 22 patients treated successfully with currently recommended regimens, replication-competent virus could be recovered routinely. The frequency of resting CD4+ T cells carrying replication-competent virus was very low (range 0.2 to 16.4 per 106) but, in cross-sectional analysis, did not decrease with increasing time on therapy. We then extended these findings by expanding the cross-sectional study and by carrying out a longitudinal study to determine a decay rate for replication-competent virus in resting CD4+ T cells in patients on HAART. Latently infected cells were detected in 33 out of 34 cases and, in a study of patients who had been treated within three months of acute infection, virus was isolated in 11 out of 12 cases. Longitudinal studies of the frequency of latently infected CD4+ T cells in 20 patients measured 2 to 7 times over the course of 7 to 21 months confirmed a very slow rate of decay for cells carrying integrated provirus. The mean half-life for this reservoir of cells was 43.9 months. At this rate, eradication of a reservoir consisting of 105 cells would take 60 years. These studies demonstrate that in a cohort of HIV-1-infected patients who have responded very well to combination therapy, the latent reservoir is established very early after primary infection and is extraordinarily stable. Latently infected CD4+ T cells thus provide a mechanism for lifelong persistence of HIV-1 and even the most effective therapies available today cannot cure infected individuals.