Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs

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Abstract
Latent HIV-1 reservoirs are established early during primary infection in CD4+ T cells and constitute a major barrier to HIV-1 eradication, even in the presence of highly active antiretroviral therapy. Resting CD4+ T cells represent an extremely restrictive environment for HIV-1 replication. By contrast, immune activation in CD4+ T cells provides an optimal environment for robust HIV-1 replication. Most factors involved in the maintenance of HIV-1 latency operate at the transcriptional level; examples include the chromosome environment at the site of integration and the availability of viral and host transcription factors. HIV-1 integration and expression can be restrained or enhanced by different host cell factors, such as inhibitor of nuclear factor-κB α-subunit (IκBα), COMMD1 (copper metabolism (Murr1) domain-containing protein 1), APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G), lens epithelium-derived growth factor (LEDGF) and emerin. Both cellular and viral microRNAs could be involved in maintaining HIV-1 latency or in controlling low ongoing viral replication. HIV-1 modifies the miRNA expression profile of the host cell and, in addition, has developed strategies to overcome the cellular miRNA restriction machinery. The existence of cellular elements that restrict retroviral replication and actively inhibit the viral transcriptional machinery provides a new paradigm for HIV-1 latency. As a result, latency should not be considered a merely passive process but rather an active process that is tightly regulated by cellular and viral factors. New insights into the molecular mechanisms of HIV-1 latency have led to the characterization of targets that are useful for designing new drugs. In particular, attractive possibilities for specific drug development include the modification of chromatin conformation through histone deacetylase inhibitors and the activation of kinase pathways that lead to the activation of transcription factors.