Abstract
Despite antiretroviral therapy (ART) which halts HIV-1 replication and reduces plasma viral load to clinically undetectable levels, viral rebound inevitably occurs once ART is interrupted. HIV-1-infected cells can undergo clonal expansion, and these clonally expanded cells increase over time. Over 50% of latent reservoirs are maintained through clonal expansion. The clonally expanding HIV-1-infected cells, both in the blood and in the lymphoid tissues, contribute to viral rebound. The major drivers of clonal expansion of HIV-1-infected cells include antigen-driven proliferation, homeostatic proliferation and HIV-1 integration site-dependent proliferation. Here, we reviewed how viral, immunologic and genomic factors contribute to clonal expansion of HIV-1-infected cells, and how clonal expansion shapes the HIV-1 latent reservoir. Antigen-specific CD4+ T cells specific for different pathogens have different clonal expansion dynamics, depending on antigen exposure, cytokine profiles and exhaustion phenotypes. Homeostatic proliferation replenishes the HIV-1 latent reservoir without inducing viral expression and immune clearance. Integration site-dependent proliferation, a mechanism also deployed by other retroviruses, leads to slow but steady increase of HIV-1-infected cells harboring HIV-1 proviruses integrated in the same orientation at specific sites of certain cancer-related genes. Targeting clonally expanding HIV-1 latent reservoir without disrupting CD4+ T cell function is a top priority for HIV-1 eradication.
Highlights
The HIV-1 latent reservoir undergoes clonal expansion The landscape of the HIV-1-infected cells is shaped by viral cytopathic effects, immune clearance and clonal expansion of the infected cells (Fig. 1a)
The fact that over 50% cells harboring infectious HIV-1 proviruses are from clonal expansion [17,18,19] suggests that other methods which can preferentially enrich for intact HIV-1 are needed to examine the HIV-1 integration site landscape of replication competent proviruses
The difference is that while antigen stimulation follows host immune homeostasis control and the HIV-1-infected clones may wane upon antigen removal, HIV-1-driven integration site-dependent proliferation will gradually increase over time (Fig. 2c), such increase may take a scale of years of in vivo selection to be observed [11, 12]
Summary
HIV-1 persists in the latent reservoir as a major barrier to cure [1,2,3]. CD4+ T cells harboring latent and transcriptionally inactive HIV-1 proviruses do not express viral antigens and do not die of viral cytopathic effects or immune clearance. While ART targets viral enzyme function or viral entry, ART does not affect HIV-1 transcription nor kills infected cells. Because of the extremely long half-life (~ 43–44 months) [4, 5] of the latent reservoir, it takes > 73 years for the latent reservoir to decay to zero [4]. All HIV-1-infected individuals need to take life-long ART. There are 37 million people living with HIV-1 and only 62% of them requiring HIV-1 treatment have access to ART [6].
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