Eradicating HIV-1 infection: seeking to clear a persistent pathogen

Abstract

Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART.

Conflict of interest statement

Competing interests statement

The authors declare competing interests: see Web version for details.

Figures

Figure 1. Mechanisms involved in the maintenance of HIV-1 latency and strategies to disrupt latency

HIV-1 latency is maintained by several mechanisms. a | Transcription factors (TFs), including nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT), are sequestered in the cytoplasm, which leads to transcriptional silencing. Bryostatin and prostratin induce activation of NF-κB, leading to its translocation to the nucleus where it activates HIV-1 transcription. b | The HIV-1 long terminal repeat (LTR) is flanked by the Nuc-0 and Nuc-1 nucleosomes that, when latent, can encode repressive post-translational histone modifications. Histone deacetylases (HDACs), which are recruited by transcription factors (such as YY1 and CBF-1), remove the acetyl groups from chromatin. Histone methyltransferases (HMTs), such as SUV39H1, G9a and EZH2, deposit methyl groups onto histones. HDACs and HMTs enforce the repressive state. Both HDAC inhibitors and HMT inhibitors can induce transcription from quiescent LTR promoters. HIV-1 DNA can also be methylated, although recent evidence suggests that DNA methylation is an epiphenomenon that does not play a part in HIV-1 latency. Bromodomain-containing (BRD) proteins have a complex role in HIV-1 transcription initiation and processivity. Recent evidence suggests that BRD2 has a unique role in enforcing HIV-1 latency, and therefore, BRD inhibitors such as JQ1 may be of use as latency-reversing agents. c | Transcriptional interference may contribute to the regulation of HIV-1 latency. If viral DNA is integrated within an intron of an upstream host gene, readthrough of RNA polymerase II (Pol II) displaces key transcription factors on the HIV-1 LTR (known as promoter occlusion). Conversely, if the viral genome is integrated in the opposite polarity relative to the host gene, host RNA Pol II complexes may induce premature termination of HIV-1 transcription (known as convergent transcription). d,e | The positive transcription elongation factor b (p-TEFb) complex (which comprises CDK9 and cyclin T1 (CycT1)) is sequestered in an inactive ribonucleoprotein complex with HEXIM1–7SK small nuclear RNA (snRNA). BRD4 may compete with the viral Tat activator for binding to p-TEFb. Hexamethylene bisacetamide (HMBA) releases p-TEFb from the HEXIM1–7SK snRNA inhibitory complex and the small-molecule inhibitor JQ1 may antagonize BRD4, both of which enable induction of latent HIV-1 expression.

Figure 2. Current model systems to study HIV-1 latency

a–c | Cell models. Cell line models (part a) are derived from immortalized T cell clones (for example, from Jurkat-derived cell lines) or promonocyte clones (for example, U1), and they have uniformly integrated copies of proviral HIV-1 DNA. By contrast, primary cell models (part b) are derived from HIV-1-negative donor CD4+ T cells, and latency is established following infection using different protocols. Studies in cells obtained from aviraemic, antiretroviral therapy (ART)-treated patients (part c) can be studied ex vivo for their response to putative latency-reversing agents and other stimuli. d,e | Humanized mouse models. Several humanized mouse models have been developed by engraftment of mice with various human tissues. Humanized severe combined immunodeficiency (SCID) mice (part d) are generated by transplanting irradiated SCID mice with human thymus and foetal liver tissue that develops into a human thymic organoid and supports HIV-1 infection, but only within this organoid. As HIV-1 replication is limited to the thymus, latency is only established in naive T cells. Engraftment of the human immune system was vastly improved with the development of the humanized NSG (NOD SCID gamma) mouse (not shown), which is generated by transplanting irradiated NOD/SCID/IL-2Rγ chain knockout mice with human CD34+ stem cells. Humanized BLT (bone marrow–liver–thymus) mice are generated by implanting human foetal thymus and liver cells into NOD SCID or NSG mice and transplantation of human CD34+ stem cells (part e). The reconstitution of the human immune system and the systemic modelling of HIV infection and latency is most robust in this mouse model. f | Non-human primate models. SIV infection in rhesus and pig-tailed macaques is similar to the progression of HIV-1 infection in humans. When susceptible, SIV-infected animals respond to ART. However, SIV is not susceptible to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and its envelope sequence is functionally divergent from that of HIV-1. The recombinant SIV viruses RT-SHIV and SHIV are aimed at overcoming these limitations using HIV-1 reverse transcriptase and envelope, respectively. RT-SHIV enables the use of clinically relevant ART combinations, and SHIV models have wider immunotherapeutic potential and can use both CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) co-receptors. PBMCs, peripheral blood mononuclear cells.

Figure 3. Strategies to eliminate latently infected cells

The induction of latent proviral expression and ensuing viral cytopathic effects may not be sufficient to clear latently infected cells. An effective eradication strategy is likely to require interventions to enhance the HIV-1-specific immune response. Approaches include in vivo administration of molecules that improve immune function and the ex vivo stimulation of cells that have been isolated from patients infected with HIV-1. a | In vivo administration of cytokines, antibodies, inhibitors of the PD-1 pathway or components of a therapeutic vaccine present a promising potential therapeutic intervention for enhancing immune responses or reversing immune exhaustion. b | Another potential strategy involves ex vivo priming of immune effectors for optimal function. Specific cell populations isolated from infected individuals, such as cytotoxic T lymphocytes (CTLs), natural killer cells or γδ T cells, are stimulated with cytokines, antibodies or HIV-1 peptides and are subsequently reinfused. c | Patient-derived effector cells can also be genetically engineered to increase their efficiency and redirect them to the desired targets. Peripheral blood cells that have been isolated from patients can be genetically modified with a molecularly cloned T cell receptor (TCR) that redirects cells to viral antigens, and T cells can be modified to express chimeric antigen receptors (CARs) with improved antigen specificity. d | Immunotoxins that consist of a targeting portion, such as an antibody or a ligand, and a toxin effector domain can be administered in vivo for targeted killing of virally infected cells. Radiolabelled antibodies that target HIV-1 proteins could deplete chronically HIV-1-infected cells. ADCC, antibody-dependent cellular cytotoxicity.

Figure 4. Barriers to HIV-1 eradication

The frequency of latently infected, resting central memory CD4+ T cells is stable in patients despite years of antiretroviral therapy (ART). Therefore, the rate of creation of these cells must closely match their rate of destruction. Although the frequency of such infected cells is proportional to the exposure to viraemia over time during initial, acute infection, the initiation of ART seems to completely block the generation of latently infected cells via new infection. As low-level viraemia seems to originate, at least in part, from the expression of virus within the latently infected central memory CD4+ T cell pool,, this latent reservoir must be maintained by one or more mechanisms, such as: new infection at extremely low frequency; the ability of some cells to resist death or clearance despite virion production; or the homeostatic or aberrant proliferation of a proportion of the cell pool without virion production and/or cell clearance.