Trends in Molecular Medicine
The multifactorial nature of HIV-1 latency
Section snippets
Two forms of HIV-1 latency
At the outset, it is important to distinguish between two forms of HIV-1 latency (Figure 1). In untreated individuals, the predominant form of HIV-1 DNA in resting CD4+ T cells is full-length, linear unintegrated DNA that represents the final product of reverse transcription 4, 24. Reverse transcription is slow in resting CD4+ T cells, requiring up to three days 25, 26. This is presumably because of low dNTP pools in these metabolically inert cells [27]. Low ATP levels might contribute to a
Post-integration latency and the nature of HIV-1 integration sites
The direct infection of resting cells does not generally proceed to integration. However, resting CD4+ T cells with integrated HIV-1 DNA can be detected in vivo 3, 4, and their phenotype suggests that they arise from infected CD4+ T lymphoblasts that have reverted to a resting memory state (Figure 1). In individuals on HAART, these resting cells do not produce virus [35]. One hypothesis is that the non-productive nature of infection in resting CD4+ T cells reflects proviral integration into
Transcriptional interference
Another potential explanation for latency, transcriptional interference (TI), is a direct consequence of the nature of HIV-1 integration sites in vivo. TI is a cis-acting suppressive effect that is observed when transcriptional activity initiated from an upstream promoter suppresses the transcription from a downstream promoter. Typically, this occurs when upstream transcription fails to terminate, so that the polymerase ‘reads through’ into the downstream gene, thereby interfering with
Availability of cellular transcription factors
HIV-1 gene expression is controlled by cellular transcription factors, as well as the HIV-1 regulatory protein Tat. Interestingly, two of the key host transcription factors are sequestered in the cytoplasm of resting T cells. Both NFAT (nuclear factor of activated T cells) and NF-κB are only recruited to the nucleus following cellular activation by T-cell receptor (TCR) engagement or cytokine signaling. In this way, HIV-1 gene expression is linked to the activation state of the host cells. NFAT
Latency and the role of HIV-1 Tat
The HIV-1 Tat protein has an important role in regulating viral gene expression [20]. Tat differs from other known eukaryotic transcriptional activators in that it recognizes and binds to RNA, not DNA, and acts at the level of elongation, not initiation [20]. The Tat protein is expressed early from a subset of multiply spliced viral RNA species. After synthesis, it is transported back into the nucleus where it binds to a stem–loop structure formed by the first 59 nucleotides of the HIV-1
Concluding remarks
HIV-1 latency represents a unique therapeutic challenge. Although the small pool of latently infected cells present in all infected individuals probably has little, if any, role in the natural history of the infection, HIV-1 eradication cannot be achieved until this pool is eliminated. However, because of the low level of HIV-1 gene expression in latently infected cells, it is very difficult to distinguish them from uninfected resting CD4+ T cells. Therefore, current efforts are focused on
Acknowledgements
This work was supported by NIH grant AI43222 and by the Doris Duke Charitable Foundation and the Howard Hughes Medical Institute.
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Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency
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