Redefining the viral reservoirs that prevent HIV-1 eradication

Abstract

This Perspective proposes definitions for key terms in the field of HIV-1 latency and eradication. In the context of eradication, a reservoir is a cell type that allows persistence of replication-competent HIV-1 on a timescale of years in patients on optimal antiretroviral therapy. Reservoirs act as a barrier to eradication in the patient population in which cure attempts will likely be made. Halting viral replication is essential to eradication, and definitions and criteria for assessing whether this goal has been achieved are proposed. The cell types that may serve as reservoirs for HIV-1 are discussed. Currently, only latently infected resting CD4(+) T cells fit the proposed definition of a reservoir, and more evidence is necessary to demonstrate that other cell types, including hematopoietic stem cells and macrophages, fit this definition. Further research is urgently required on potential reservoirs in the gut-associated lymphoid tissue and the central nervous system.

Figure 1

Plasma virus levels in untreated and treated HIV-1 infection. Virus production continues throughout the course of untreated HIV-1 infection (top panel). Levels of viremia vary widely between patients but average between 10,000 and 100,000 copies/ml. Stable reservoirs make a very small contribution to overall virus production. Their contribution, apparent only when active replication is halted by HAART, is around 1 copy/ml (Palmer et al., 2003; Palmer et al., 2008). HAART induces a rapid biphasic drop in the level of viremia (bottom panel), reflecting the rapid turnover of the cells that produce most of the plasma virus (Ho et al., 1995; Perelson et al., 1996; Perelson et al., 1997; Wei et al., 1995). Eradication strategies will likely be implemented in patients who have had suppression of viremia to below the limit of detection for >1 year to allow decay of these labile infected cell populations.

Figure 2

Distinguishing ongoing viral replication from virus production by latently infected cells that have been activated. A variety of parameters have been evaluated to determine whether a low degree of viral replication continues in patients on HAART. These are indicated in red and include expression of HIV-1 RNA, residual viremia, labile products of reverse transcription such as linear unintegrated HIV-1 DNA, LTR circles, and the accumulation of mutations (viral evolution). Depending on the HAART regimen, some of these parameters can also reflect the reactivation of latently infected cells without further replication (bottom panel). For example, in patients on regimens in which an integrase inhibitor is the most active drug, all of these features except evolution would be present. Only the accumulation of new mutations is uniquely characteristic of ongoing replication.