The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence

Abstract

Combination antiretroviral therapy (ART) for HIV-1 infection reduces plasma virus levels to below the limit of detection of clinical assays. However, even with prolonged suppression of viral replication with ART, viremia rebounds rapidly after treatment interruption. Thus, ART is not curative. The principal barrier to cure is a remarkably stable reservoir of latent HIV-1 in resting memory CD4(+) T cells. In this review, we consider explanations for the remarkable stability of the latent reservoir. Stability does not appear to reflect replenishment from new infection events but rather normal physiologic processes that provide for immunologic memory. Of particular importance are proliferative processes that drive clonal expansion of infected cells. Recent evidence suggests that in some infected cells, proliferation is a consequence of proviral integration into host genes associated with cell growth. Efforts to cure HIV-1 infection by targeting the latent reservoir may need to consider the potential of latently infected cells to proliferate.

Figure 1

Model for the establishment of latent HIV-1 infection in resting memory CD4⁺ T cells. The normal process of memory cell generation (boxed) involves the exposure of a resting CD4⁺ T cells to antigen which leads to blast transformation, proliferation, and differentiation into effector cells. Many effector cells die during the contraction phase of the immune response, but a fraction survive and gradually return to a quiescent state as long-lived resting memory cells. Most resting CD4⁺ T cells lack expression of CCR5, a critical coreceptor for HIV-1 entry. Activation of resting cells by antigen (Ag) upregulates CCR5 expression and reverses other blocks to HIV-1 replication in resting CD4⁺ T cells, allowing productive infection of these cells. Most productively infected CD4⁺ T lymphoblasts die rapidly from activation-induced cells death (AICD), viral cytopathic effects (CPE), or lysis by CTL. As activated cells transition back to a resting state, active forms of key host transcription factors needed for HIV-1 gene expression are sequestered. Infection at this stage may lead to latent infection rather than cell death. Other models posit direct infection of resting cells. Please see text for references.

Figure 2

Dynamics of the latent reservoir. ART largely blocks new infection of susceptible cells. In patients on long term ART, the pool of latently infected cells is extremely stable (t½ = 3.7 years) so that memory cell turnover must be largely balanced by proliferation of previously infected cells. Latently infected resting memory CD4⁺ T cells occasionally encounter the relevant cognate antigen (or a cross-reacting antigen) and become activated. Activation reverses latency, allowing viral gene expression and virus production. In patients on ART, the released viruses do not successfully infect new cells, but may be detected at very low levels in the plasma where they constitute the residual viremia (RV). Most productively infected cells die quickly from AICD, CPE, or lysis by CTL. It is possible that some degree of antigen-driven proliferation may occur without activation of viral gene expression. Homeostatic proliferation of memory cells may also occur without reactivating viral gene expression. For some infected cells, integration of the provirus into genes associated with cell growth may also stimulate proliferation. See text for references.