HIV persistence in the setting of antiretroviral therapy: when, where and how does HIV hide?

Abstract

Advances in the treatment of HIV infection have dramatically reduced the death rate from AIDS and improved the quality of life of many HIV-infected individuals. However, the possible long-term toxicity associated with antiretroviral therapy (ART), stigma and cost, all contribute to the necessity of finding a cure for HIV infection. In infected individuals taking ART, HIV persists in a small number of cells that can survive for the lifetime of the infected person. These persistently infected cells, usually referred as the 'reservoirs for HIV infection', are the main barriers to a cure. The diversity of the tissues and cellular types in which HIV persists, as well as the multiplicity of the molecular mechanisms contributing to HIV persistence, complicate the efforts to develop a safe, effective, and globally accessible cure for HIV. In this review, we summarise recent data that contribute to our understanding of HIV persistence during ART by addressing three questions pertaining to the HIV reservoir: (1) when is the reservoir established; (2) where is the reservoir maintained; and (3) how does the reservoir persist?

Keywords: CD4+ T cells; HIV cure; HIV latency; HIV reservoir; acute infection; molecular mechanisms; tissues.

Figure 1.

Clinical definition of the HIV reservoir. Untreated HIV infection is characterised by high levels of viral replication that can be measured in the plasma of HIV-infected individuals. ART reduces viral replication to undetectable levels by standard viral load measurements. When ART is interrupted, HIV replication resumes, revealing that HIV persisted in cellular and anatomical ‘reservoirs’ during ART and that these reservoirs can re-ignite infection.

Figure 2.

Contribution of CD4+ T cell subsets to the HIV reservoir during ART. CD4+ T cell subsets can be classified according to their differentiation and memory status (top) or to their effector functions (bottom). Cell-surface markers and the production of specific cytokines can be used to identify each individual subset. The relative contribution of each subset to the HIV reservoir is indicated. (Adapted from Geginat et al. Semin Immunol 2013; 25: 252–262; Geginat et al. Front Immunol 2014; 16 Dec 2014.)