The multifactorial nature of HIV-1 latency

doi:10.1016/j.molmed.2004.09.006

Trends in Molecular Medicine

Volume 10, Issue 11, November 2004, Pages 525-531

https://doi.org/10.1016/j.molmed.2004.09.006 Get rights and content

HIV-1 can avoid host immune responses and antiretroviral drugs through the latent infection of resting memory CD4⁺ T cells. Recently, latent viral genomes have been shown to reside within the introns of active host genes. Therefore, latency is not simply due to an inaccessibility of the integrated proviruses to the transcriptional machinery. Rather, latency might result from insufficient nuclear levels of the crucial activation-dependent host transcription factors required to overcome the transcriptional interference that is an automatic consequence of the nature of HIV-1 integration sites. In addition, resting cells lack sufficient levels of HIV-1 Tat and Tat-associated activation-dependent host factors that are necessary for processive transcription. Defects at consecutive steps of transcriptional initiation and elongation enable HIV-1 to remain hidden within resting CD4⁺ T cells.

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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Trends in Molecular Medicine

The multifactorial nature of HIV-1 latency

Section snippets

Two forms of HIV-1 latency

Post-integration latency and the nature of HIV-1 integration sites

Transcriptional interference

Availability of cellular transcription factors

Latency and the role of HIV-1 Tat

Concluding remarks

Acknowledgements

Immunity

Cell

Cell

Cell

Cell

Cell

Immunity

Curr. Opin. Immunol.

Mol. Cell

Virology

J. Biol. Chem.

J. Biol. Chem.

Blood

Immunity

High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR

Science

Fate of HIV-1-infected T cells in vivo: Rates of transition to stable latency

Nat. Med.

Quantitation of latent tissue reservoirs and total body load in HIV-1 infection

Nature

Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy

Science

Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy

Proc. Natl. Acad. Sci. U. S. A.

Recovery of replication-competent HIV despite prolonged suppression of plasma viremia

Science

Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy

Nat. Med.

Long term follow-up studies confirm the extraordinary stability of the latent reservoir for HIV-1 in resting CD4+ T cells

Nat. Med.

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence

Proc. Natl. Acad. Sci. U. S. A.

Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure

J. Virol.

The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation

EMBO J.

HIV reproducibly establishes a latent infection after acute infection of T cells in vitro

EMBO J.

An inducible transcription factor activates expression of human immunodeficiency virus in T cells

Nature

Human immunodeficiency virus long terminal repeat responds to T-cell activation signals

Proc. Natl. Acad. Sci. U. S. A.

Tumor necrosis factor α activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-κB sites in the long terminal repeat

Proc. Natl. Acad. Sci. U. S. A.

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J. Virol.

Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat

Mol. Cell. Biol.

Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product

Nature

Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts

Proc. Natl. Acad. Sci. U. S. A.

Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor

J. Virol.

Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection

Science

Molecular characterization of preintegration latency in HIV-1 infection

J. Virol.

Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes

J. Virol.

Active nuclear import of human immunodeficiency virus type 1 preintegration complexes

Proc. Natl. Acad. Sci. U. S. A.

Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes

J. Exp. Med.

Latent infection of CD4⁺ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy

Long term follow-up studies confirm the extraordinary stability of the latent reservoir for HIV-1 in resting CD4⁺ T cells