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HIV

Since the initial isolation of HIV more than 30 years ago, research has elucidated the viral life cycle, how HIV interacts with its host and the mechanisms of pathogenesis. Alongside these seminal discoveries, anti-retroviral drugs and additional treatment options have been developed that aim to prevent and cure HIV infection. Despite this progress, the AIDS pandemic is still ongoing; approximately 37 million people are infected with HIV worldwide, and infection remains incurable. With this collection, we hope to bring renewed attention to the latest developments in HIV research and how they are affecting efforts towards prevention, treatment and cure. 

The collection combines Reviews and Research articles recently published across several Nature journals. It also includes links to additional content, such as recent News articles and previous Special Focuses on HIV. Finally, you can find information on the Nature webinar that marks the 2015 World AIDS Day: “Eliminating HIV: bringing together prevention, treatment and cure”, featuring Steven Deeks (UCSF), Susan Buchbinder (UCSF) and Robert Siliciano (Johns Hopkins).

The content of this collection has been chosen by the editors of Nature Reviews Microbiology.

In two separate papers, Massimo Pizzato and colleagues and Heinrich Göttlinger and colleagues identify previously unrecognized restriction factors for HIV-1. In the absence of the HIV-1 Nef protein, the multipass transmembrane proteins SERINC3 and SERINC5 become incorporated into assembling virions and profoundly block HIV-1 infection. The Nef protein, which is normally expressed by HIV-1, counteracts this activity by down-regulating SERINC3 and SERINC5 from the cell surface, thereby preventing their incorporation into virions. These findings identify SERINC5, and to a lesser extent SERINC3, as the agents responsible for the long-sought anti-HIV-1 activity that is overcome by Nef. This raises the possibility that SERINC5 might have potential as a basis for anti-HIV-1 therapeutics.

Article | | Nature

In two separate papers, Massimo Pizzato and colleagues and Heinrich Göttlinger and colleagues identify previously unrecognized restriction factors for HIV-1. In the absence of the HIV-1 Nef protein, the multipass transmembrane proteins SERINC3 and SERINC5 become incorporated into assembling virions and profoundly block HIV-1 infection. The Nef protein, which is normally expressed by HIV-1, counteracts this activity by down-regulating SERINC3 and SERINC5 from the cell surface, thereby preventing their incorporation into virions. These findings identify SERINC5, and to a lesser extent SERINC3, as the agents responsible for the long-sought anti-HIV-1 activity that is overcome by Nef. This raises the possibility that SERINC5 might have potential as a basis for anti-HIV-1 therapeutics.

Article | | Nature

Infection by human immunodeficiency virus type 1 (HIV-1) requires the integration of the viral genome into host DNA, and the virus is known to integrate preferentially into a subset of transcriptionally active genes. Mauro Giacca and colleagues report here that nuclear location influences target gene selection. They show that hotspots preferentially targeted by the virus are more commonly found in the outer shell of the nucleus proximal to the nuclear pore rather than centrally, implying that perhaps because of the short half-life of HIV-1 integrase, the virus interacts with the first open chromatin regions it encounters on its route into the nucleus.

Letter | | Nature

The passive administration of broadly neutralizing antibodies (bNAbs) to HIV has been effective against HIV-1 infection in humanized mice and macaque models of HIV-1 infection. It has been suggested that bNAbs, administered passively or by viral vectors, may be effective for prevention and immunotherapy in humans. The safety and efficacy of the approach had not been tested in humans previously but here Michel Nussenzweig and colleagues report the results of a phase I study of passive immunization with neutralizing antibodies directed at CD4 binding sites, and show that the treatment transiently reduces HIV viral loads in humans.

Letter | | Nature

Antiretroviral therapy does not cure HIV-1 infection: despite drug treatment, most patients still have latent reservoirs of the virus. This study of immune cells isolated from 30 HIV-1-infected patients who had been on antiretroviral therapy for at least two years and had maintained undetectable plasma HIV-1 RNA levels, shows that these viral reservoirs are dominated by viruses with cytotoxic T lymphocyte escape mutations. This finding implies that future directions in therapeutic vaccine design may need to focus on boosting broad cytotoxic T lymphocyte responses.

Letter | | Nature

Reservoirs of virus infection, impervious to antiviral drugs, are a serious obstacle to attempts to eradicate human immunodeficiency virus type 1 (HIV-1). Dan Barouch and colleagues explore the timing of the formation of these reservoirs in a monkey model. They find that antiviral treatment as early as three days after infection of macaques with simian immunodeficiency virus — prior to the onset of viraemia — fails to prevent the seeding of viral reservoirs, and the virus eventually rebounds when drug treatment is discontinued.

Letter | | Nature

This study describes a novel class of highly potent HIV-1 entry inhibitors that can be delivered with a gene-therapy vector to provide an effective alternative to conventional vaccines for HIV-1. To enter cells, HIV-1 first binds its cellular receptor CD4, then the co-receptor CCR5 or CXCR4 The new entry inhibitor consists of the immunoadhesin CD4-Ig fused to a sulfopeptide mimicking CCR5. This fusion, called eCD4-Ig, avidly binds the Env protein of HIV-1 and irreversibly inactivates it. Michael Farzan and colleagues show that this inhibitor has exceptional potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1. When delivered to macaques using an adeno-associated virus, it can protect them from multiple challenges with virus.

Letter | | Nature

Our understanding of immature HIV — the form of the virus leaves the cell — is based on purified components assembled in vitro in a manner thought to mimic the true state. Here John Briggs and colleagues resolve the structure of the protein shell within intact heterogeneous immature HIV-1 particles. Using cryo-electron tomography and sub-tomogram averaging (averaging thousands of aligned sub-volumes containing the same structural unit), the authors determine the structure of the capsid lattice at at 8.8 Å. The structure shows that the arrangement of capsid in immature HIV-1 is very different from that seen in the mature HIV-1 capsid core, and reveals the tertiary and quaternary interactions that mediate HIV-1 assembly.

Letter | | Nature

The human protein APOBEC3G (A3G) inhibits HIV-1 replication, but the viral protein Vif counteracts by inducing A3G degradation. Here Miyakawa et al. show that the antiretroviral drug AZT restores A3G function in vitroby stimulating expression of a host protein, ASK1, which interferes with the action of Vif.

Article | Open Access | | Nature Communications

The elimination of latently infected cells is a sought after goal in the treatment of HIV-1 infections. Here the authors develop an approach to eliminate latently HIV-1 infected cells by using an immunomodulatory protein, which can activate viral gene expression in these cells and direct T lymphocytes to lyse them in vitro.

Article | Open Access | | Nature Communications