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Viral reservoirs pose a major challenge in the efforts towards curing HIV. Here, Churchill, Deeks, Margolis, Siliciano and Swanstrom discuss the cells and tissues that constitute the viral reservoir, how best to measure it and how to target this source of persistent infection.

Resting T cells are difficult to manipulate, and are a reservoir for latent HIV. Here, the authors develop a lipid nanoparticle formulation with the ability to transfect resting primary human T cells, enabling delivery of mRNAs that result in reactivation of latent HIV. This could help development of HIV cure strategies.

Steven G. Deeks and Françoise Barré-Sinoussi present an international research agenda to seek out a cure for AIDS.

Gao and colleagues explore soluble biomarkers, immune cell subsets, viral antibody responses and plasma proteomics to better define and understand long COVID in two independent cohorts.

HIV reservoir decay is less well studied in acute infection. Here, the authors show that reservoir decay rates are biphasic and 5x faster in people initiating antiretroviral therapy during acute HIV than prior estimates for chronic HIV. Higher initial CD4+ counts and lower viral loads predicted faster decay.

The development of effective antiretroviral therapies has greatly improved the disease prognosis for patients with HIV. However, the limitations of these therapies have renewed interest in developing alternative treatment strategies. Here, a group of experts from the International AIDS Society discuss the research steps that need to be taken to achieve the ultimate objective — a cure for HIV.

Biological determinants for developing post-acute sequelae of SARS-CoV-2 infection are largely unclear. Here, by comparing markers during acute infection in individuals who developed PASC with those who recovered, the authors found that early viral dynamics and immune responses might play a role in PASC pathogenesis.

Understanding the heterogeneity of HIV infection, such as in persons with non-suppressible HIV-1 viremia despite adherence to antiretroviral treatment, is crucial to better tailor therapeutic interventions to abrogate HIV-1 persistence.

Siliciano and colleagues describe the generation of bispecific antibodies that target the HIV-1 envelope protein (Env) on the surface of HIV-1-infected cells and the receptor CD16 on the surface of NK cells to induce the NK cell-mediated lysis of HIV-1-infected cells and reduce the viral reservoir.

In this Review, Landovitz, Scott and Deeks explore the current state of the art for HIV prevention and treatment, including unmet needs and emerging tools. They describe how researchers are combining different approaches, such as prevention, treatment and cure, to achieve better outcomes in the fight against the HIV/AIDS epidemic.

The authors used mathematical modeling of human data to study how HIV persists despite suppressive antiretroviral therapy. They found that when latently infected CD4+ T cells proliferate or differentiate, they can create HIV DNA and passage it into other subsets. More mature CD4 cell subsets then clear HIV DNA faster.

Quantifying intact proviruses is key to understanding decreases in HIV reservoirs but results can differ depending on the method. To balance sensitivity and specificity of two assays, the authors use mathematical models and measurements of intact and defective proviruses to assess how misclassification can impact estimates of natural and therapeutic reservoir reduction.

Rebound virus in the cerebrospinal fluid of a human cohort is a possible HIV-1 reservoir.

CD8⁺ T cell responses have been associated with control of HIV replication, but the role of CD4⁺ T cells in protecting against this virus is unclear. In an analysis of HLA class II–restricted CD4⁺ T cell responses in HIV-infected individuals, Hendrik Streeck and his colleagues now report that certain HLA-DRB1 variants are associated with low viremia and can present a wide breadth of peptides, suggesting that CD4⁺ T cell responses in infected individuals may help control HIV.

HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population of cells with transcriptomic patterns that favour HIV silencing, cell survival and cell proliferation.

An effective and scalable cure strategy is a top priority for the HIV research field; this Review discusses recent advances, knowledge gaps, and priority research areas for the next 5 years.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Here, the authors apply positron emission tomography (PET) imaging to visualize HIV tissue-wide burden in infected individuals using a radiolabeled broadly neutralizing antibody, ⁸⁹Zr-VRC01, and show that PET tracer lymph node uptake positively correlates with HIV protein levels measured directly from cells obtained from these tissues. This strategy may allow non-invasive characterization of residual HIV infection in the setting of therapeutic interventions.

Even during effective treatment with antiretroviral drugs, low levels of HIV persist. In part, this could be due to cell-to-cell transfer of multiple virions and the drugs' inability to inhibit replication when virus levels are high. See Letter p.95

Efforts to make a prophylactic HIV vaccine have identified monoclonal antibodies that potently suppress viral replication. Studies in monkeys show that these reagents effectively treat HIV infection. See Article p.224 & Letter p.277

Antiretroviral therapies block HIV replication but they do not eliminate inactive viruses within cells. A clinical trial shows that a drug can revive HIV in patients as a potential first step towards a cure. See Letter p.482

The human leukocyte antigen allele HLA-B*15:01 is associated with asymptomatic SARS-CoV-2 infection due to pre-existing T cell immunity.

In individuals who have achieved natural control of HIV-1 without drug treatment, intact proviral sequences are integrated into genomic regions that are not permissive to active viral transcription, indicating deep latency of the virus.

The immune checkpoint molecule PD-1 is expressed on a fraction of CD4⁺ T cells latently infected with HIV, but whether PD-1 plays a functional role in reservoir persistence remains unknown. Here, Fromentin et al. show that PD-1 blockade potentiates latency reversal ex vivo in CD4⁺ T cells from ART suppressed individuals.

Multiple genetic variants have been identified that influence the outcome of HIV infection. Carrington and colleagues investigate the mechanism of one of the strongest variants, rs1015164, and show that it influences expression of a lncRNA controlling CCR5 expression.

Distinct roadblocks prevent translating basic findings in viral pathogenesis into therapies and implementing potential solutions in the clinic. An ongoing partnership between the Volkswagen Foundation and Nature Medicine resulted in an interactive meeting in 2012, as part of the “Herrenhausen Symposia” series. Current challenges for various fields of viral research were recognized and discussed with a goal in mind—to identify solutions and propose an agenda to address the translational barriers. Here, some of the researchers who participated at the meeting provide a concise outlook at the most pressing unmet research and clinical needs, identifying these key obstacles is a necessary step towards the prevention and cure of human viral diseases.

Transplantation of human hematopoietic stem cells engineered to lack the viral coreceptor CCR5 confers resistance to HIV infection in mice.

This study describes the mechanisms of FOXO1-mediated repression of endoplasmic reticulum (ER) stress in HIV-1 latency. The authors propose a model where inhibition of FOXO1 activity promotes protein accumulation in the ER leading to ER stress signalling and calcium release, which mobilizes ATF4 and NFAT and activates HIV-1 transcription.

The International AIDS Society Towards a Cure Working Group lays out its scientific strategy to achieve a cure for HIV.

Quantifying the total-body virus burden in HIV-infected individuals is necessary to understand viral persistence and guide development of cure strategies. Here, Estes et al. find a high burden of residual virus in tissues of SIV-infected monkeys and HIV-infected humans, and evidence of low-level viral replication, even under antiretroviral therapy.

HIV-1 infection is associated with persistent inflammation that can contribute to a variety of comorbidities. Luban and colleagues demonstrate that HIV-1 infection results in permanent depletion of innate lymphoid cells, leading to breakdown of gut barrier function and a feed-forward inflammation loop, which includes skewing of NK cells toward an inflammatory/memory phenotype.

Mary Carrington and colleagues follow up on an earlier association of a variant upstream of HLA-C to HIV viral load setpoint, showing that this variant is associated with high HLA-C cell surface expression and demonstrating a protective effect of the variant in viral load and disease progression.

Roan et al. use Olink and single‐cell RNA sequencing (scRNA-seq) to show a dysregulated crosstalk between the cellular and humoral immune responses in individuals with long COVID 8 months postinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Despite receiving antiretroviral therapy, most patients with HIV still have latent reservoirs of the virus; here, these reservoirs are shown to be dominated by viruses with cytotoxic T lymphocyte escape mutations, with potential implications for the development of therapeutic vaccines.

Bruner et al. report that defective HIV-1 proviruses predominate in early infection, even when antiretroviral therapy is initiated in the first months after infection. The results highlight challenges in estimating the reservoir of intact, replication-competent virus that may influence cure strategies.

The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health (NIH), convened a virtual workshop on August 8-9^th, 2023 to explore potential synergies between HIV vaccine approaches that are designed to induce cellular or humoral immune responses. The goal of this workshop was to review data on leading vaccine candidates and to discuss the best strategies for combining these approaches to optimize immunity against HIV. Here, we summarize the findings reviewed at the workshop and discuss the knowledge gaps and priorities for future studies that will help accelerate the development of a preventive HIV vaccine.

Current barriers and limitations to HIV treatments are reviewed, and suggestions for future steps to achieve an effective curative intervention are discussed.

Millions of people are infected with human immunodeficiency virus (HIV) globally. Antiretroviral therapy offers substantial benefit to those infected or at risk of infection — controlling viraemia and delaying the onset of acquired immune deficiency syndrome (AIDS). Here, the authors describe the basic and clinical research advances in this important global health issue.

An assay to measure the latent HIV-1 reservoir that separately quantifies intact and defective proviruses will facilitate evaluation of HIV-1 cure strategies by measuring the provirues that pose a barrier to cure.

Autoreactive T cells are subject to continuous antigenic stimulation yet sustain their autoreactive functionality. Youngblood and colleagues examine type 1 diabetes systems to show that a pool of autoreactive CD8⁺ T cells exhibits a stem cell–like signature that facilitates their durable activity.