HIV

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.

The isolation of HIV-1 was a fundamental step for understanding HIV and the disease it causes. Here, Françoise Barré-Sinoussi, Anna Laura Ross and Jean-François Delfraissy look back on three decades of research that have changed the lives of people infected with HIV and have inspired hope for a cure.

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.

In this Review, Campbell and Hope describe the interactions between the HIV-1 capsid core and several cellular factors that enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and viral integration into the genome of the target cell.

Combination antiretroviral therapy (cART) has revolutionized the treatment of HIV-1 infection, but the mechanistic basis of successful treatment is poorly understood. In this Opinion article, Siliciano and Laskey present a model to assess the efficacy of antiretroviral drugs and argue that this is a more accurate metric to predict the success of cART than current metrics.

Recent efforts have focused on the development of therapies that could eradicate HIV-1 infection or achieve a durable remission of viraemia in the absence of antiretroviral therapy; however, targeting viral quiescence within specific cellular reservoirs so that residual infection can be cleared remains a challenge. In this Review, Margolis and colleagues explore new approaches to eradicate established HIV-1 infection.

In this Review, Malim and colleagues discuss the evidence that type I interferons (IFNs) can control HIV-1 replicationin vivoand debate the controversial role of IFNs in promoting the pathological sequelae of chronic HIV-1 infection.

HIV-1 infection typically results from the transmission of a single viral variant, the transmitted/founder (T/F) virus. In this Review, Joseph and colleagues discuss how studying these T/F viruses contributes to a better understanding of HIV-1 transmission and affects prevention strategies.

In this Opinion article, the authors provide an overview of the recent work that has been carried out investigating broadly neutralizing HIV-1 antibodies and their thoughts on the future prospects of the antibody-based prevention of HIV-1 infection.

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.

In this Opinion article, Dan Barouch and Louis Picker discuss recent data regarding the clinical development of novel serotype adenovirus and cytomegalovirus vaccine vectors for use in HIV-1 vaccines.

Although studies in 2D cell culture systems have provided great insights into the biology and pathogenesis of HIV-1 infection, such studies cannot account for many aspects of host physiology that affect HIV-1in vivo. Fackler et al. discuss the development and application of more integrative studies, including organotypic 3D culture systems, small-animal models and advanced live-cell imaging, and the impact of such studies on our understanding of the mechanisms of HIV-1 spread.

Kirchhoff and colleagues discuss the discovery of novel antimicrobial peptides by systematic screening of complex peptide and protein libraries that have been derived from human bodily fluids and tissues, with a focus on the isolation of endogenous agents that affect HIV-1 infection.

Erectile dysfunction (ED) is often overlooked in men with HIV, despite its high prevalence in affected men of all ages. In this Review, Santi and colleagues discuss the aetiology and social issues associated with ED in men with HIV, and provide useful advice for the clinician treating such patients.

HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection. However, with multiple direct acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients. In this Review, the authors address the epidemiology, natural history, pathogenesis and management of HIV and HCV co-infection.

HIV infection is associated with renal diseases including HIV-associated nephropathy, HIV-immune-complex kidney disease, thrombotic microangiopathy and disorders associated with nephrotoxic HIV therapies. Here, the authors review the epidemiology, histopathology, mechanisms, genetic susceptibility, diagnosis and treatment of HIV-associated nephropathies and highlight remaining questions for future research.

Combination antiretroviral therapy (cART) has substantially prolonged the lives of patients with HIV infection, but these individuals have an increased risk of coronary heart disease and myocardial infarction compared with uninfected individuals. In this Review, Reiss and colleagues discuss the control of both traditional and immune risk factors, and the appropriate selection of cART regimens, to reduce the risk of cardiovascular complications in patients with HIV.

In this Review, Heyns et al. provide an update on the urological complications associated with HIV and AIDS in men treated during the ART era, focusing on papers published within the past decade.

The transmembrane proteins SERINC3 and SERINC5 are identified as new restriction factors for HIV-1 replication; this restriction is counteracted by Nef and glycoGag, which prevent SERINC3 and SERINC5 from becoming incorporated into HIV-1 virions and from profoundly blocking HIV-1 infectivity, suggesting a potential new therapeutic strategy for immunodeficiency viruses.

The transmembrane protein SERINC5 is identified as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef; Nef redirects SERINC5 from the plasma membrane to a Rab7-positive endosomal compartment, thus excluding it from HIV-1 particles, emphasizing the potential of SERINC5 as a potent anti-retroviral factor.

HIV-1 integration into the host cell genome occurs in the outer shell of the nucleus in close correspondence with the nuclear pore, in which a series of cellular genes are preferentially targeted by the virus.

A phase I study of passive immunization with a CD4 binding-site-directed broadly neutralizing antibody shows that it transiently reduces HIV-1 viral loads in humans.

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.

Reservoirs of virus infection represent the most important reason why HIV-1 cannot be cured with current antiretroviral drugs; now the refractory viral reservoir is shown to be seeded as early as 3 days after infection in a monkey model, even before the virus is detected in the blood.

The new entry inhibitor eCD4-Ig, consisting of the immunoadhesin form of CD4 (CD4-Ig) fused to a small CCR5-mimetic sulfopeptide, avidly binds two highly conserved sites of the HIV-1 Env protein; the inhibitor has high potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1 viruses, and when delivered to macaques using an adeno-associated virus vector, it can provide effective long-term protection from multiple challenges with simian/human immunodeficiency virus.

Cryo-electron tomography and subtomogram averaging methods reveal the structure of the capsid lattice within intact heterogeneous immature HIV-1 particles.

Fukazawa et al. report that SIV persists in follicular helper T cells in elite controller macaques, evading clearance by CD8+ T cells

Morgane Rolland and colleagues report that in HIV infection, a higher diversity of infecting founder viruses is associated with markers of poorer clinical outcome.

The CRISPR/Cas9 system can be used for genome editing. Here, Liao et al. show that the system can be adapted to inhibit HIV expression and replication, excise the integrated HIV genome and provide long-term protection against new infections in human cells, including pluripotent stem cells.

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.

In some HIV-1-infected individuals, viraemia remains undetectable after antiretroviral treatment, but which of these patients will experience viral rebound is difficult to predict. Here the authors show that T cell exhaustion markers before treatment are predictive of shorter time to viral rebound.

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.

The structure of the ligand-free HIV-1–Env trimer allows conformational fixation of Env and generation of an antigen that binds CD4 with high affinity and is recognized by broadly neutralizing antibodies but not poorly neutralizing ones.

Evolution- and structure-guided mutagenesis allows elucidation of the solution NMR structure of the N-terminal domain of APOBEC3G. Mapping of HIV-1 Vif binding to the APOBEC3G NTD reveals an interaction interface distinct from those in other APOBEC3 proteins.

Peptide hydrocarbon stapling is used to generate protease-resistant HIV-1 MPER antigens that mimic the conformation of viral epitopes and that are recognized by two different broadly neutralizing antibodies to HIV.