Abstract
HIV-1 is extremely specialized since, even amongst CD4+ T lymphocytes (its major natural reservoir in peripheral blood), the virus productively infects only a small proportion of cells under an activated state. As the percentage of HIV-1-infected cells is very low, most studies have so far failed to capture the precise transcriptomic profile at the whole-genome scale of cells highly susceptible to virus infection. Using Affymetrix Exon array technology and a reporter virus allowing the magnetic isolation of HIV-1-infected cells, we describe the host cell factors most favorable for virus establishment and replication along with an overview of virus-induced changes in host gene expression occurring exclusively in target cells productively infected with HIV-1. We also establish that within a population of activated CD4+ T cells, HIV-1 has no detectable effect on the transcriptome of uninfected bystander cells at early time points following infection. The data gathered in this study provides unique insights into the biology of HIV-1-infected CD4+ T cells and identifies genes thought to play a determinant role in the interplay between the virus and its host. Furthermore, it provides the first catalogue of alternative splicing events found in primary human CD4+ T cells productively infected with HIV-1.
Highlights
CD4+ T cells – the primary cellular target of HIV-1 – are progressively depleted over the course of infection
Following the design of a unique and innovative molecular tool to identify cells productively infected with HIV-1 and the description of an efficient magnetic beads-based technique to separate them from uninfected bystander cells, we undertake this challenge and perform the first comparative whole-genome transcriptomic and large-scale proteomic profiling of both HIV-1-infected and uninfected bystander CD4+ T cells
We found that Th1 and Th17 were to some extent more permissive to virus infection in this specific in vitro experimental setting
Summary
CD4+ T cells – the primary cellular target of HIV-1 – are progressively depleted over the course of infection. This long-term process culminates in the onset of AIDS, a condition in which the immune system is too weak to efficiently mount an effective defence against opportunistic pathogens. HIV-1 uses only 15 proteins to disable the natural immune defences and harness the host cell machinery to complete its replicative cycle. The apoptosis rate of uninfected bystander CD4+ T cells is elevated in individuals carrying HIV-1 [1]. The dichotomy between uninfected bystander and HIV-1-infected CD4+ T cells is an important topic to study, as a deeper understanding of HIV-1 pathogenesis mechanisms might lead to new therapeutic approaches
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