Current opinion in HIV and AIDS最新文献

Purpose of review: Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and reignite viral replication if therapy is interrupted. Persistence of the viral reservoir in people with HIV-1 (PWH) is the main obstacle to an HIV-1 cure. The reservoirs are not transcriptionally silent, and viral transcripts can be detected in most ART-treated individuals. Here, we review the recent progress in the characterization of persistent HIV-1 transcription during ART.

Recent findings: Evidence from several studies indicates that, although cell-associated unspliced (US) HIV-1 RNA is abundantly expressed in ART-treated PWH, intact full-length US transcripts are rare and most US RNA is derived from defective proviruses. The transcription- and translation-competent defective proviruses, previously considered irrelevant, are increasingly being linked to residual HIV-1 pathogenesis under suppressive ART. Recent data suggest a continuous crosstalk between the residual HIV-1 activity under ART and the immune system. Persistent HIV-1 transcription on ART, despite being mostly derived from defective proviruses, predicts viral rebound upon therapy interruption, suggesting its role as an indicator of the strength of the host antiviral immune response that is shaping the viral rebound.

Summary: In light of the recent findings, the significance of persistent HIV-1 transcription during ART for the long-term health of PWH and the cure research should be reassessed.

Purpose of review: The purpose of this article is to review recent advances in the role of natural killer (NK) cells in approaches aimed at reducing the latent HIV-1 reservoir.

Recent findings: Multiple approaches to eliminate cells harboring latent HIV-1 are being explored, but have been met with limited success so far. Recent studies have highlighted the role of NK cells and their potential in HIV-1 cure efforts. Anti-HIV-1 NK cell function can be optimized by enhancing NK cell activation, antibody dependent cellular cytotoxicity, reversing inhibition of NK cells as well as by employing immunotherapeutic complexes to enable HIV-1 specificity of NK cells. While NK cells alone do not eliminate the HIV-1 reservoir, boosting NK cell function might complement other strategies involving T cell and B cell immunity towards an HIV-1 functional cure.

Summary: Numerous studies focusing on targeting latently HIV-1-infected cells have emphasized a potential role of NK cells in these strategies. Our review highlights recent advances in harnessing NK cells in conjunction with latency reversal agents and other immunomodulatory therapeutics to target HIV-1 persistence.

Purpose of review: This review highlights advances in understanding the epigenetic control mechanisms that regulate HIV-1 latency mechanisms in T-cells and microglial cells and describes the potential of current therapeutic approaches targeting the epigenetic machinery to eliminate or block the HIV-1 latent reservoir.

Recent findings: Large-scale unbiased CRISPR-Cas9 library-based screenings, coupled with biochemical studies, have comprehensively identified the epigenetic factors pivotal in regulating HIV-1 latency, paving the way for potential novel targets in therapeutic development. These studies also highlight how the bivalency observed at the HIV-1 5'LTR primes latent proviruses for rapid reactivation.

Summary: The HIV-1 latent is established very early during infection, and its persistence is the major obstacle to achieving an HIV-1 cure. Here, we present a succinct summary of the latest research findings, shedding light on the pivotal roles played by host epigenetic machinery in the control of HIV-1 latency. Newly uncovered mechanisms permitting rapid reversal of epigenetic restrictions upon viral reactivation highlight the formidable challenges of achieving enduring and irreversible epigenetic silencing of HIV-1.

Purpose of the review: The central nervous system (CNS) is an hotspot for HIV persistence and may be a major obstacle to overcome for curative strategies. The peculiar anatomical, tissular and cellular characteristics of the HIV reservoir in the CNS may need to be specifically addressed to achieve a long-term HIV control without ART. In this review, we will discuss the critical challenges that currently explored curative strategies may face in crossing the blood-brain barrier (BBB), targeting latent HIV in brain-resident myeloid reservoirs, and eliminating the virus without eliciting dangerous neurological adverse events.

Recent findings: Latency reversing agents (LRA), broadly neutralizing monoclonal antibodies (bNabs), chimeric antigen receptor (CAR) T-cells, and adeno-associated virus 9-vectored gene-therapies cross the BBB with varying efficiency. Although brain penetration is poor for bNAbs, viral vectors for in vivo gene-editing, certain LRAs, and CAR T-cells may reach the cerebral compartment more efficiently. All these approaches, however, may encounter difficulties in eliminating HIV-infected perivascular macrophages and microglia. Safety, including local neurological adverse effects, may also be a concern, especially if high doses are required to achieve optimal brain penetration and efficient brain cell targeting.

Summary: Targeting the CNS remains a potential problem for the currently investigated HIV curing strategies. In vivo evidence on CNS effectiveness is limited for most of the investigated strategies, and additional studies should be focused on evaluating the interplay between the cerebral HIV reservoir and treatment aiming to achieve an ART-free cure.

Purpose of review: To underline the complexity and the heterogeneity of the HIV reservoir.

Recent findings: While lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue) harbor specific subsets of specialized CD4 +  T cells enriched in HIV-infected cells, non-CD4 +  T cell reservoirs such as tissue-resident macrophages and dendritic cells have also been implicated to contribute to viral persistence. Moreover, studies have applied highly sensitive tools to detect transcriptional activity within HIV-infected cells during prolonged ART and revealed a broader spectrum of transcriptional activity for proviruses than previously thought. Finally, while a combination of factors might be involved in the regulation of HIV persistence within different tissues and remains to be fully elucidated, recent results from autopsy samples of HIV-infected ART suppressed individuals indicate extensive clonality of HIV reservoirs in multiple tissues and suggest that the recirculation of HIV-infected cells and their local expansions in tissues may also contribute to the complexity of the HIV reservoirs in humans.

Summary: HIV persistence in blood and multiple tissues despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on its composition, viral diversity, tissue distribution, transcriptional activity, replication competence, migration dynamics and proliferative potential across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.

Purpose of review: Despite decades of insights about how CD8 + T cells and natural killer (NK) cells contribute to natural control of infection, additional hurdles (mutational escape from cellular immunity, sequence diversity, and hard-to-access tissue reservoirs) will need to be overcome to develop a cure. In this review, we highlight recent findings of novel mechanisms of antiviral cellular immunity and discuss current strategies for therapeutic deisgn.

Recent findings: Of note are the apparent converging roles of viral antigen-specific MHC-E-restricted CD8 + T cells and NK cells, interleukin (IL)-15 biologics to boost cytotoxicity, and broadly neutralizing antibodies in their native form or as anitbody fragments to neutralize virus and engage cellular immunity, respectively. Finally, renewed interest in myeloid cells as relevant viral reservoirs is an encouraging sign for designing inclusive therapeutic strategies.

Summary: Several studies have shown promise in many preclinical models of disease, including simian immunodeficiency virus (SIV)/SHIV infection in nonhuman primates and HIV infection in humanized mice. However, each model comes with its own limitations and may not fully predict human responses. We eagerly await the results of clinical trails assessing the efficacy of these strategies to achieve reductions in viral reservoirs, delay viral rebound, or ultimately elicit immune based control of infection without combination antiretroviral therapy (cART).

Purpose of review: HIV requires lifelong antiviral treatment due to the persistence of a reservoir of latently infected cells. Multiple strategies have been pursued to promote the death of infected cells.

Recent findings: Several groups have focused on multipronged approaches to induce apoptosis of infected cells. One approach is to combine latency reversal agents with proapoptotic compounds and cytotoxic T cells to first reactivate and then clear infected cells. Other strategies include using natural killer cells or chimeric antigen receptor cells to decrease the size of the reservoir.A novel strategy is to promote cell death by pyroptosis. This mechanism relies on the activation of the caspase recruitment domain-containing protein 8 (CARD8) inflammasome by the HIV protease and can be potentiated by nonnucleoside reverse transcriptase inhibitors.

Summary: The achievement of a clinically significant reduction in the size of the reservoir will likely require a combination strategy since none of the approaches pursued so far has been successful on its own in clinical trials. This discrepancy between promising in vitro findings and modest in vivo results highlights the hurdles of identifying a universally effective strategy given the wide heterogeneity of the HIV reservoirs in terms of tissue location, capability to undergo latency reversal and susceptibility to cell death.

Purpose of review: We explore the current status of research on HIV-1 subtype-specific variations and their impact on HIV-1 latency. We also briefly address the controversy surrounding the decision-making process governing the ON/OFF states of HIV-1 transcription, specifically focusing on the regulatory elements, the long terminal repeat (LTR), and Tat. Understanding the decision-making process is crucial for developing effective intervention strategies, such as the 'shock-and-kill' approach, to reactivate latent HIV-1.

Recent findings: Attention has been drawn to subtype-specific transcription factor binding site (TFBS) variations and the possible impact of these variations on viral latency. Further, diverse subtype-specific assays have been developed to quantify the latent viral reservoirs. One interesting observation is the relatively larger latent reservoirs in HIV-1B infection than those of other viral subtypes, which needs rigorous validation. The emergence of LTR-variant viral strains in HIV-1C demonstrating significantly higher levels of latency reversal has been reported.

Summary: Despite persistent and substantial efforts, latent HIV-1 remains a formidable challenge to a functional cure. Determined and continued commitment is needed to understand the ON/OFF decision-making process of HIV-1 latency, develop rigorous assays for accurately quantifying the latent reservoirs, and identify potent latency-reversing agents and cocktails targeting multiple latency stages. The review emphasizes the importance of including diverse viral subtypes in future latency research.