International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing life-long therapy to a global population of over 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2–9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow–liver–thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal—in combination with appropriate tools for systemic clearance of persistent HIV infection—greatly increases opportunities for HIV eradication

Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus1–4. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8+ lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8+ lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8+ T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4+ T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Polymorphisms in Rhesus Macaque Tetherin Are Associated with Differences in Acute Viremia in Simian Immunodeficiency Virus Δnef-Infected Animals

ABSTRACT Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. To determine the extent of sequence variation and the impact of polymorphisms in rhesus macaque tetherin on simian immunodeficiency virus (SIV) infection, tetherin alleles were sequenced from 146 rhesus macaques, including 68 animals infected with wild-type SIVmac239 and 47 animals infected with SIVmac239Δnef. Since Nef is the viral gene product of SIV that counteracts restriction by tetherin, these groups afford a comparison of the effects of tetherin polymorphisms on SIV strains that are, and are not, resistant to tetherin. We identified 15 alleles of rhesus macaque tetherin with dimorphic residues at 9 positions. The relationship between these alleles and plasma viral loads was compared during acute infection, prior to the onset of adaptive immunity. Acute viremia did not differ significantly among the wild-type SIV-infected animals; however, differences in acute viral loads were associated with polymorphisms in tetherin among the animals infected with SIVΔnef. In particular, polymorphisms at positions 43 and 111 (P43 and H111) were associated with lower acute-phase viral loads for SIVΔnef infection. These observations reveal extensive polymorphism in rhesus macaque tetherin, maintained perhaps as a consequence of variability in the selective pressure of diverse viral pathogens, and identify tetherin alleles that may have an inherently greater capacity to restrict SIV replication in the absence of Nef. IMPORTANCE As a consequence of ongoing evolutionary conflict with viral pathogens, tetherin has accumulated numerous species-specific differences that represent important barriers to the transmission of viruses between species. This study reveals extensive polymorphism in rhesus macaque tetherin and identifies specific alleles that are associated with lower viral loads during the first few weeks after infection with nef-deleted SIV. These observations suggest that the variable selective pressure of viral pathogens, in addition to driving the diversification of tetherin among species, also operates within certain species to maintain sequence variation in tetherin

Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV‐1 Transcription in a Phase IIb Trial

Disulfiram (DSF) was well tolerated and activated viral transcription (cell-associated unspliced (CA-US) and plasma human immunodeficiency virus (HIV) RNA) in a phase II dose-escalation trial in HIV+ antiretroviral therapy (ART)-suppressed participants. Here, we investigated whether exposure to DSF and its metabolites predicted these changes in HIV transcription. Participants were administered 500 (N = 10), 1,000 (N = 10), or 2,000 (N = 10) mg of DSF for 3 consecutive days. DSF and four metabolites were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Changes in CA-US and plasma HIV RNA were quantified by polymerase chain reaction (PCR) and analyzed in NONMEM. A seven-compartment pharmacokinetic (PK) model demonstrated nonlinear elimination kinetics. The fitted median area under the curve values for 72 hours (AUC0-72 ) were 3,816, 8,386, and 22,331 mg*hour/L, respectively. Higher exposure predicted greater increases in CA-US (maximum effect (Emax ) = 78%, AUC50  = 1,600 μg*hour/L, P = 0.013) but not plasma HIV RNA. These results provide support for further development of DSF as an important drug for future HIV cure strategies

The use of nonhuman primate models in HIV vaccine development.

Cecilia Morgan and colleagues outline a two-stage nonhuman primate screening strategy for T cell-based HIV-1 vaccines

Trends and Predictors of Cigarette Smoking Among HIV Seropositive and Seronegative Men: The Multicenter Aids Cohort Study

We measured the trend of cigarette smoking among HIV-seropositive and seronegative men over time from 1984-2012. Additionally, we examined the demographic correlates of smoking and smoking consumption. 6,577 men who have sex with men (MSM) from the Multicenter AIDS Cohort Study (MACS) were asked detailed information about their smoking history since their visit. Prevalence of smoking and quantity smoked was calculated yearly from 1984-2012. Poisson regression with robust error variance was used to estimate prevalence ratios of smoking in univariate and multivariate models. In 2012, 11.8% and 36.9% of men who were enrolled in the MACS before 2001 or during or after 2001 smoked cigarettes, respectively. In the multivariate analysis, black, non-Hispanic, lower education, enrollment wave, alcohol use, and marijuana use were positively associated with current smoking in MSM. HIV serostatus was not significant in the multivariate analysis. However, HIV variables, such as detectable viral load, were positively associated. Though cigarette smoking has declined over time, the prevalence still remains high among subgroups. There is still a need for tailored smoking cessation programs to decrease the risk of smoking in HIV-seropositive men who have sex with men