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Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021
Despite the success of antiretroviral therapy (ART) for people living with HIV, lifelong treatment is required and there is no cure. HIV can integrate in the host genome and persist for the life span of the infected cell. These latently infected cells are not recognized as foreign because they are largely transcriptionally silent, but contain replication-competent virus that drives resurgence of the infection once ART is stopped. With a combination of immune activators, neutralizing antibodies, and therapeutic vaccines, some nonhuman primate models have been cured, providing optimism for these approaches now being evaluated in human clinical trials. In vivo delivery of gene-editing tools to either target the virus, boost immunity or protect cells from infection, also holds promise for future HIV cure strategies. In this Review, we discuss advances related to HIV cure in the last 5 years, highlight remaining knowledge gaps and identify priority areas for research for the next 5 years.
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.
Journal Article
Prolonged viral suppression with anti-HIV-1 antibody therapy
HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4
+
T cells
1
. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells
2
,
3
. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml
−1
. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.
A clinical study shows that immunotherapy with anti-HIV-1 antibodies maintains prolonged viral suppression after anti-retroviral treatment is discontinued and affects the size and composition of the intact but not the defective proviral reservoir.
Journal Article
HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor
HIV-1 infection requires nuclear entry of the viral genome. Previous evidence suggests that this entry proceeds through nuclear pore complexes (NPCs), with the 120 × 60 nm capsid squeezing through an approximately 60-nm-wide central channel
1
and crossing the permeability barrier of the NPC. This barrier can be described as an FG phase
2
that is assembled from cohesively interacting phenylalanine–glycine (FG) repeats
3
and is selectively permeable to cargo captured by nuclear transport receptors (NTRs). Here we show that HIV-1 capsid assemblies can target NPCs efficiently in an NTR-independent manner and bind directly to several types of FG repeats, including barrier-forming cohesive repeats. Like NTRs, the capsid readily partitions into an in vitro assembled cohesive FG phase that can serve as an NPC mimic and excludes much smaller inert probes such as mCherry. Indeed, entry of the capsid protein into such an FG phase is greatly enhanced by capsid assembly, which also allows the encapsulated clients to enter. Thus, our data indicate that the HIV-1 capsid behaves like an NTR, with its interior serving as a cargo container. Because capsid-coating with
trans
-acting NTRs would increase the diameter by 10 nm or more, we suggest that such a ‘self-translocating’ capsid undermines the size restrictions imposed by the NPC scaffold, thereby bypassing an otherwise effective barrier to viral infection.
The HIV-1 capsid behaves like a nuclear transport receptor entering and traversing an FG phase, with its interior serving as a cargo container, bypassing an otherwise effective barrier to viral infection.
Journal Article
Shh! We're writing the Constitution
Describes how the Constitution came to be written and ratified. Also includes the full text of the document produced by the Constitutional Convention of 1787.
Book
Origins and evolutionary consequences of ancient endogenous retroviruses
Retroviruses infect a broad range of vertebrate hosts that includes amphibians, reptiles, fish, birds and mammals. In addition, a typical vertebrate genome contains thousands of loci composed of ancient retroviral sequences known as endogenous retroviruses (ERVs). ERVs are molecular remnants of ancient retroviruses and proof that the ongoing relationship between retroviruses and their vertebrate hosts began hundreds of millions of years ago. The long-term impact of retroviruses on vertebrate evolution is twofold: first, as with other viruses, retroviruses act as agents of selection, driving the evolution of host genes that block viral infection or that mitigate pathogenesis, and second, through the phenomenon of endogenization, retroviruses contribute an abundance of genetic novelty to host genomes, including unique protein-coding genes and cis-acting regulatory elements. This Review describes ERV origins, their diversity and their relationships to retroviruses and discusses the potential for ERVs to reveal virus–host interactions on evolutionary timescales. It also describes some of the many examples of cellular functions, including protein-coding genes and regulatory elements, that have evolved from ERVs.Vertebrate genomes typically contain thousands of loci composed of ancient retroviral sequences, known as endogenous retroviruses (ERVs). In this Review, Johnson describes ERV origins, their diversity and their relationships to retroviruses and discusses the potential for ERVs to reveal virus–host interactions on evolutionary timescales. He also describes examples of cellular functions, including protein-coding genes and regulatory elements that have evolved from ERVs.
Journal Article
HIV-1 assembly, release and maturation
Key Points
The HIV-1 Gag polyprotein precursor is necessary and sufficient for the formation of virus-like particles in Gag-expressing cells. Gag contains domains that are required for virus assembly and release: the matrix (MA) domain directs Gag to the plasma membrane and promotes the incorporation of the viral envelope (Env) glycoproteins; the capsid (CA) domain drives Gag–Gag interactions during assembly; the nucleocapsid (NC) domain packages the viral genomic RNA; and the p6 domain is required for efficient particle release.
HIV-1 recruits several host factors to promote virus assembly and release. For example, the endosomal sorting complex required for transport (ESCRT) machinery is recruited by the p6 domain of Gag to mediate the pinching off of virus particles from the cell.
Shortly after virus release from the cell, the viral protease cleaves the Gag precursor into the mature Gag proteins MA, CA, NC and p6. Gag processing is a highly ordered multistep sequential process that triggers the morphological rearrangement of viral protein structure, which is known as maturation.
The Gag protein has been the focus of drug discovery efforts aimed at developing inhibitors that are distinct from those targeting the viral enzymes protease, reverse transcriptase and integrase. Of particular promise are small-molecule inhibitors of capsid function, and maturation inhibitors, which target a late step in Gag processing.
In this article, Eric Freed reviews recent progress in elucidating the steps involved in HIV-1 assembly, release and maturation, highlighting how these events are orchestrated by the viral Gag precursor protein and how this information is being used to develop novel anti-HIV-1 therapeutics.
Major advances have occurred in recent years in our understanding of HIV-1 assembly, release and maturation, as work in this field has been propelled forwards by developments in imaging technology, structural biology, and cell and molecular biology. This increase in basic knowledge is being applied to the development of novel inhibitors designed to target various aspects of virus assembly and maturation. This Review highlights recent progress in elucidating the late stages of the HIV-1 replication cycle and the related interplay between virology, cell and molecular biology, and drug discovery.
Journal Article