Residual Human Immunodeficiency Virus Type 1 Viremia in Some Patients on Antiretroviral Therapy Is Dominated by a Small Number of Invariant Clones Rarely Found in Circulating CD4 ⁺ T Cells

Abstract

Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4؉ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4 ؉ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4 ؉ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4 ؉ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4 ؉ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4 ؉ T cells.Treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART) reduces viremia to below the detection limit of ultrasensitive clinical assays (15,16,37). However, HIV-1 persists in resting CD4 ϩ T cells (6,8,9,12,51) and possibly other reservoirs (4, 58). The latent reservoir in resting CD4ϩ T cells has a long half-life (11,41,44,47,56) that will likely preclude virus eradication unless novel approaches (5, 24-28, 42) can purge latently infected cells.In patients on HAART, HIV-1 persistence is evidenced not only by the latent reservoir in resting CD4 ϩ T cells but also by free virus in the plasma (10,17,19,36,41,48,52). Free virions can be found with special methods, even in patients who do not have clinically detectable viremia (10,18,19,36,52). Given the short half-life of free virus (20,49), this residual viremia indicates active virus production. This virus production may reflect low-level ongoing replication that continues despite HAART (7,10,13,14,18,21,33,48,56) and/or release of virus from latently infected cells that become activated (19,22,34,48,55) or from other stable cellular reservoirs (4, 58). The characterization of residual viremia may provide a means for determining the importance of different mechanisms of viral persistence.Although the presence of free virus can be detected ...

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