HIV Cure Research Articles

Antibodies Tip the Balance Towards an HIV Cure

Long-term drug therapy for HIV-1 infection can prevent both disease progression and virus transmission, but treatment does not eradicate the virus. A new gene therapy study (Immunity 2019;50:567-575.e5) using human antibodies shows significant promise for a functional cure in a non-human primate model.

Impact of Myeloid Reservoirs in HIV Cure Trials.

Gallant efforts are ongoing to achieve sustained antiretroviral therapy (ART)-free HIV remission in the HIV-infected person; however, most, if not all, current human clinical studies have primarily focused these efforts on targeting viral persistence in CD4 T cells in blood and tissue sanctuaries. The lack of myeloid centered HIV clinical trials, either as primary or secondary end points, has hindered our understanding of the contribution of myeloid cells in unsuccessful trials but may also guide successes in future HIV eradication clinical strategies. Recent advances have highlighted the importance of myeloid reservoirs as sanctuaries of HIV persistence and therefore may partially be responsible for viral recrudescence following ART treatment interruption in several clinical trials where HIV was not detectable or recovered from CD4 T cells. Given these findings, novel innovative therapeutic approaches specifically focused on HIV clearance in myeloid cell populations need to be vigorously pursued if we are to achieve additional cases of sustained ART-free remission. This review will highlight new research efforts defining myeloid persistence and recent advances in HIV remission and cure trials that would be relevant in targeting this compartment and make an argument as to their clinical relevancy as we progress towards sustained ART-free HIV remission in all HIV-infected persons.

Editorial introductions

Editorial introductions

What causes non-adherence among some individuals on long term antiretroviral therapy? Experiences of individuals with poor viral suppression in Uganda

BackgroundAntiretroviral therapy (ART) use by people living with HIV reduces HIV transmission, morbidity, mortality, and improves quality of life. Good ART adherence is required to achieve these benefits. We investigated how the environmental, social, economic and behavioural experiences of people living with HIV with poor viral suppression could explain their non-adherence to long term ART.MethodsThis qualitative cross-sectional study was conducted in Uganda between September 2015 and April 2016. Thirty individuals on ART for 5 years or more (10 on first line and 20 on second line), with poor viral suppression, were randomly selected from a cohort of people living with HIV on ART. In-depth interviews about ART; awareness, adherence counselling, obstacles to daily adherence and regimen switches were conducted. Emerging themes from the interviews transcripts and field notes were identified and thematic content analysis done. Participants’ consent, compensation, confidentiality and study ethical approvals were ensured.ResultsWe found that poor adherence to long term ART was due to: travel for work or social activities, stigma, receiving little or no continuous ART adherence education, alcohol consumption and use of alternative ‘HIV cure’ medicines. Other reasons included; ART side effects, treatment fatigue, belief that long-term ART or God can ‘cure HIV’, and food security.ConclusionsAchieving optimal ART benefits requires continuous provision of ART adherence education to individuals on long term ART. This helps them overcome the challenges related to living with HIV: worries of food insecurity, alcohol misuse, economic hardship, and beliefs in HIV cures and use of unproven alternative HIV treatments. People living with HIV who travel require adherence support and larger quantities of ART refills to cover their time away.

Kick and Kill Approach: How Far are we from HIV Cure?

Kick and Kill Approach: How Far are we from HIV Cure?

Applying the Functional Behavioral and Social Sciences Research (BSSR) Framework to HIV Cure Research

Applying the Functional Behavioral and Social Sciences Research (BSSR) Framework to HIV Cure Research

Putting Participants at the Centre of HIV Cure Research

Putting Participants at the Centre of HIV Cure Research

Highlights from the Fourth Biennial Strategies for an HIV Cure Meeting, 10–12 October 2018, Bethesda, MD, USA

The National Institute of Allergy and Infectious Diseases (NIAID) organised the Strategies for an HIV Cure 2018 meeting focused on research to develop innovative strategies for eradicating or achieving long-term remission of HIV infection. The purpose was to bring together researchers studying HIV persistence and cure strategies, including the six National Institutes of Health (NIH)-funded Martin Delaney Collaboratories for HIV Cure Research (MDCs), as well as industry and community partners, to share scientific results and stimulate active discussion among all stakeholders about the merits of various approaches under investigation. These discussions were intended to stimulate new collaborations and ideas for future research. The meeting covered a comprehensive range of topics spanning basic and translational research, drug discovery and development, and clinical research. Aside from the oral presentations described here, the meeting also included 130 poster presentations. Each of the three days of presentations is available for viewing via the NIH VideoCast website at: https://videocast.nih.gov/PastEvents.asp.

HIV Cure Strategies: A Complex Approach for a Complicated Viral Reservoir?

HIV Cure Strategies: A Complex Approach for a Complicated Viral Reservoir?

1767. Structured Treatment Interruptions in HIV-Infected Patients Receiving Antiretroviral Therapy—Implications for Future HIV Cure Trials: A Systematic Review and Meta-analysis

BackgroundSafety and tolerability of analytical treatment interruption (TI) as part of HIV cure studies has been discussed controversially. In this systematic review and meta-analysis, we report current evidence for the occurrence of adverse effects during different types of TI.MethodsA systematic literature search on studies reporting on TIs was conducted using a defined search term, covering the period from January 1988 to May 2017. All interventional and observational studies were reviewed, and results were extracted based on predefined criteria. We evaluated the proportion of adverse effects during TI by using a random effect meta-analysis model. A meta-regression model was calculated to explore the variation across studies and the influence of key factors.ResultsWe identified 1,048 studies, of which we obtained data from 24 studies investigating TI including 7,961 individuals. Sample sizes varied from 6 to 5,472 subjects. The number of reported events during TI ranged from 0 to 241. Follow-up intervals during TI varied from 2 days up to 3 months. We compared reported adverse effects in studies with long TI (>4 weeks) by the lengths of follow-up intervals, comparing narrow (≤4 weeks) and wide (>4 weeks) follow-up during TI. The proportion of patients exhibiting adverse events during long TI was 1% (95% CI 0–4, I2 = 24.9%) in studies with narrow and 10% (95% CI 5–117, I2 = 95.1%) in studies with wide follow-up intervals, with an overall reported rate of 5% (95% CI: 3–15, z = 3.93, P ≤ 0.00) (Figure 1). The number of reported deaths was relatively low, but higher in studies with wide follow-up compared with studies with narrow follow-up (Figure 2). Meta regression analysis indicated that adverse events were increasing with the length of the monitoring interval (β = 0.75, 95% CI 0.24–1.27, P = 0.007) (Figure 3).ConclusionCurrent evidence indicates that studies with narrow follow-up intervals did not show a substantial increase of adverse effects other than viral rebound during TI. Analytical treatment interruption may be a safe strategy as part of HIV cure trials if patients undergo intense follow-up routines. Disclosures All authors: No reported disclosures.

HIV Cure Research: An example of successful advocacy by scientists for science.

Following medical school and an internal medicine residency in Toronto, and infec-tious diseases training at the New England Medical Center/Tufts University in Boston, Jonathan joined the Division of Infectious Diseases, Department of Medicine at the Ottawa General Hospital in 1995. His research focuses on understanding how HIV damages the immune system and how these insights may lead to new therapies. Jon-athan is currently Professor of Medicine, University of Ottawa and Senior Scientist, Ottawa Hospital Research Institute. He was Editor-in-Chief of CIM from 2010-2015.

Strategies for an HIV cure: progress and challenges.

The ‘Strategies for an HIV Cure’ conference was held 27–28 April 2018 in Beijing, China, and was hosted by The People's Republic of China Ministry of Science and Technology and the Chinese Academy of Sciences.

Synthetic DNA delivery by electroporation promotes robust in vivo sulfation of broadly neutralizing anti-HIV immunoadhesin eCD4-Ig.

BackgroundDespite vigorous and ongoing efforts, active immunizations have yet to induce broadly neutralizing antibodies (bNAbs) against HIV-1. An alternative approach is to achieve prophylaxis with long-term expression of potent biologic HIV-1 inhibitors with Adeno-associated Virus (AAV), which could however be limited by hosts' humoral and cellular responses. An approach that facilitates in vivo production of these complex molecules independent of viral-vectored delivery will be a major advantage.MethodsWe used synthetic DNA and electroporation (DNA/EP) to deliver an anti-HIV-1 immunoadhesin eCD4-Ig in vivo. In addition, we engineered a TPST2 enzyme variant (IgE-TPST2), characterized its intracellular trafficking patterns and determined its ability to post-translationally sulfate eCD4-Ig in vivo.FindingsWith a single round of DNA injection, a peak expression level of 80-100μg/mL was observed in mice 14 days post injection (d.p.i). The engineered IgE-TPST2 enzyme trafficked efficiently to the Trans-Golgi Network (TGN). Co-administrating low dose of plasmid IgE-TPST2 with plasmid eCD4-Ig enhanced the potency of eCD4-Ig by three-fold in the ex vivo neutralization assay against the global panel of HIV-1 pseudoviruses.InterpretationThis work provides a proof-of-concept for delivering anti-HIV-1 immunoadhesins by advanced nucleic acid technology and modulating protein functions in vivo with targeted enzyme-mediated post-translational modifications.FundingThis work is supported by NIH IPCAVD Grant U19 Al109646-04, Martin Delaney Collaboration for HIV Cure Research and W.W. Smith Charitable Trust.

Barriers for HIV Cure: The Latent Reservoir.

Thirty-five years after the identification of HIV-1 as the causative agent of AIDS, we are still in search of vaccines and treatments to eradicate this devastating infectious disease. Progress has been made in understanding the molecular pathogenesis of this infection, which has been crucial for the development of the current therapy regimens. However, despite their efficacy at limiting active viral replication, these drugs are unable to purge the latent reservoir: a pool of cells that harbor transcriptionally inactive, but replication-competent HIV-1 proviruses, and that represent the main barrier to eradicate HIV-1 from affected individuals. In this review, we discuss advances in the field that have allowed a better understanding of HIV-1 latency, including the diverse cell types that constitute the latent reservoir, factors influencing latency, tools to study HIV-1 latency, as well as current and prospective therapeutic approaches to target these latently infected cells, so a functional cure for HIV/AIDS can become a reality.

Indirect Benefits in HIV Cure Clinical Research: A Qualitative Analysis.

Currently, much of early phase HIV cure research involves unknown and potentially serious risks, with little or no chance of direct health benefits. During informed consent, researchers emphasize this lack of personal medical benefit to minimize misconceptions that undermine genuine consent. We explored participants' and researchers' perspectives on HIV cure clinical research participation and its potential benefits. We conducted semistructured interviews with 17 HIV cure research participants and nine researchers in North Carolina, USA. We analyzed interviews to identify participant experience-related themes. We were particularly interested in indirect benefits, such as psychological support or improved care. We also assessed five consent documents for benefit/risk-related language. Research participants were male, with a median age of 50 (range: 28-62); most were non-Hispanic white (15/17) and men who have sex with men (13/17). All 17 trial participants found research participation meaningful and beneficial. Reported benefits included improved healthcare (16/17), HIV knowledge (13/17), intimate relationships (10/17), and positive behaviors (6/17). In addition, all participants described psychological benefits, including increased positive outlook, improved sense of purpose, emotional support, and enriched self-image. Participants reported risks such as quality of life concerns, uncomfortable procedures (e.g., leukapheresis), latency reversal, and HIV status disclosure. While the consent documents included discussion of these and other risks, they did not mention potential indirect benefits. Individuals involved in HIV clinical research have recognized participant psychological, social, and behavioral benefits. We recommend that researchers and institutional review boards consider these benefits for inclusion during risk/benefit assessments, consent procedures, and other discussions with prospective participants.

Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure.

Antiretroviral therapy regimens durably suppress HIV replication, but do not cure infection. This is partially attributable to the persistence of long-lived pools of resting CD4+ T-cells harboring latent replication-competent virus. Substantial clinical and pre-clinical research is currently being directed at purging this viral reservoir by combining pharmacological latency reversal with immune effectors, such as HIV-specific CD8+ T-cells, capable of eliminating reactivated targets—the so-called “shock-and-kill” approach. However, several studies indicate that the latency-reversing agents (LRAs) may affect CD8+ T-cell function. The current review aims to frame recent advances, and ongoing challenges, in implementing “shock-and-kill” strategies from the perspective of effectively harnessing CD8+ T-cells. We review and contextualize findings indicating that LRAs often have unintended impacts on CD8+ T-cell function, both detrimental and beneficial. We identify and attempt to bridge the gap between viral reactivation, as measured by the detection of RNA or protein, and bona fide presentation of viral antigens to CD8+ T-cells. Finally, we highlight factors on the effector (CD8+) and target (CD4+) cell sides that contribute to whether or not infected-cell recognition results in killing/elimination. These perspectives may contribute to an integrated view of “shock-and-kill,” with implications for therapeutic development.

Do Immune Checkpoint Inhibitors Have a Role in HIV Cure Trials

Immune checkpoint inhibitors, such as anti-PD-1 antibodies, have transformed the treatment of many malignancies. In people with HIV on antiretroviral

PIN57 - Prior Perceptions and Subsequent Decisional Conflict Regarding HIV Cure Trial Participation in Bangkok, Thailand

Studies of clinical and research decision making and decision satisfaction often measure participant-reported decision conflict as an outcome. As part of our longitudinal study in an HIV cohort, we examine the relationship between pre-existing perceptions and subsequent decision conflict among those accepting and declining trial participation. We conducted a baseline questionnaire in a cohort of individuals diagnosed with acute HIV in Bangkok, Thailand, prior to their recruitment to a cure trial. Questions included respondents’ perceptions of anticipated benefits and harms of HIV cure trials, and a rating of their intention to participate in a hypothetical trial that includes interruption of antiretroviral therapy. During the following 16-24 months, individuals were offered participation in one of three HIV cure trials. Joiners and decliners completed the Decisional Conflict Scale (DCS) during longitudinal interviews starting at participation offer and concluding shortly after trial completion. We categorized participants into high, medium, or low decisional conflict levels based on their most recent DCS score. Using ordinal logistic regression, we examined the relationship between decisional conflict category and pre-existing perceptions using a partial proportional odds model. Of 250 participants completing the baseline questionnaire, 74 have been offered participation in one of three trials, and consented to interviews. Baseline assessment of potential trial participation benefit to the individual, potential benefit to science, and the participants’ intention to participate in a trial all were correlated with decision conflict score, while potential risk to self was not. When participants’ most recent decision conflict scores were categorized, ordinal regression indicated the strongest association between intention to participate and subsequent decision conflict category. Participant or decliner status was not associated with decision conflict. Our results suggest a strong impact of baseline intention to participate on later decision conflict for trial joiners and decliners, consistent with several other studies.

Lymph Node Cellular and Viral Dynamics in Natural Hosts and Impact for HIV Cure Strategies

Combined antiretroviral therapies (cARTs) efficiently control HIV replication leading to undetectable viremia and drastic increases in lifespan of people living with HIV. However, cART does not cure HIV infection as virus persists in cellular and anatomical reservoirs, from which the virus generally rebounds soon after cART cessation. One major anatomical reservoir are lymph node (LN) follicles, where HIV persists through replication in follicular helper T cells and is also trapped by follicular dendritic cells. Natural hosts of SIV, such as African green monkeys and sooty mangabeys, generally do not progress to disease although displaying persistently high viremia. Strikingly, these hosts mount a strong control of viral replication in LN follicles shortly after peak viremia that lasts throughout infection. Herein, we discuss the potential interplay between viral control in LNs and the resolution of inflammation, which is characteristic for natural hosts. We furthermore detail the differences that exist between non-pathogenic SIV infection in natural hosts and pathogenic HIV/SIV infection in humans and macaques regarding virus target cells and replication dynamics in LNs. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host’s LNs, such as NK cell-mediated control, that will be reviewed here, together with lessons and limitations of in vivo cell depletion studies that have been performed in natural hosts. Finally, we discuss the impact that these insights on viral dynamics and host responses in LNs of natural hosts have for the development of strategies toward HIV cure.

Regulatory T Cells As Potential Targets for HIV Cure Research.

T regulatory cells (Tregs) are a key component of the immune system, which maintain a delicate balance between overactive responses and immunosuppression. As such, Treg deficiencies are linked to autoimmune disorders and alter the immune control of pathogens. In HIV infection, Tregs play major roles, both beneficial and detrimental. They regulate the immune system such that inflammation and spread of virus through activated T cells is suppressed. However, suppression of immune activation also limits viral clearance and promotes reservoir formation. Tregs can be directly targeted by HIV, thereby harboring a fraction of the viral reservoir. The vital role of Tregs in the pathogenesis and control of HIV makes them a subject of interest for manipulation in the search of an HIV cure. Here, we discuss the origin and generation, homeostasis, and functions of Tregs, particularly their roles and effects in HIV infection. We also present various Treg manipulation strategies, including Treg depletion techniques and interventions that alter Treg function, which may be used in different cure strategies, to simultaneously boost HIV-specific immune responses and induce reactivation of the latent virus.