Abstract
Highly active antiretroviral therapy (HAART) suppresses human immunodeficiency virus (HIV) replication to undetectable levels but cannot fully eradicate the virus because a small reservoir of CD4+ T cells remains latently infected. Since HIV efficiently infects only activated CD4+ T cells and since latent HIV primarily resides in resting CD4+ T cells, it is generally assumed that latency is established when a productively infected cell recycles to a resting state, trapping the virus in a latent state. In this study, we use a dual reporter virus—HIV Duo-Fluo I, which identifies latently infected cells immediately after infection—to investigate how T cell activation affects the estab-lishment of HIV latency. We show that HIV latency can arise from the direct infection of both resting and activated CD4+ T cells. Importantly, returning productively infected cells to a resting state is not associated with a significant silencing of the integrated HIV. We further show that resting CD4+ T cells from human lymphoid tissue (tonsil, spleen) show increased latency after infection when compared to peripheral blood. Our findings raise significant questions regarding the most commonly accepted model for the establishment of latent HIV and suggest that infection of both resting and activated primary CD4+ T cells produce latency.
Highlights
Once highly active antiretroviral therapy (HAART) became available in 1995, human immunodeficiency virus (HIV) infection was transformed from a deadly disease into a chronic lifelong condition [1]
Latent HIV is primarily found within memory CD4+ T cells, which have a long half-life in vivo [11, 12], allowing latent virus to persist within infected individuals for decades [13]
The literature is replete with conflicting reports on whether resting CD4+ T cells can be infected by HIV, either productively or latently [23]
Summary
Once highly active antiretroviral therapy (HAART) became available in 1995, HIV infection was transformed from a deadly disease into a chronic lifelong condition [1]. HAART cannot eradicate HIV [5] because infected individuals harbor a small reservoir of latently infected cells that contain a transcriptionally silent but reactivatable provirus [6] Because this latent reservoir prevents viral eradication, there is an urgent need to study and better understand the mechanisms of latency. When latently infected memory CD4+ T cells encounter an antigen or are exposed to specific cytokines or chemokines, proviral transcription is activated, leading to productive infection [8, 14]. This “reactivation” is likely the cause of viral rebound after a patient stops HAART, and it explains why infected individuals must take antiretroviral drugs for life
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