Abstract
The XVIII International Conference of the International AIDS Society held in Vienna on the 18–23 July 2010 brought together scientists, clinicians, policymakers, people living with HIV/AIDS and journalists from across the globe. Keynote speakers relevant to the theme of this report included Sharon Lewin (Alfred Hospital, Melbourne, Australia) and Tae-Wook Chun (National Institute of Allergy and Infectious Diseases, MA, USA), among others. A total of 19,100 delegates from across 193 countries attended the conference, which comprised 248 sessions, accompanied by 6238 abstracts and posters. The remit was broad, covering scientific, social and political aspects of the HIV/AIDS epidemic. This article focuses on the issue of eliminating latent reservoirs of HIV-1 infection, highlighting selected potential novel therapeutic interventions in overcoming challenges in HIV-1 suppression.
HIV reservoirs: what are the strategies for elimination?
As Sharon Lewin (Alfred Hospital, Melbourne, Australia) noted in her conference opening ceremony address, HIV therapeutics may need to move away from the infectious disease model of ‘sterilizing cure’ towards an oncology model. For example, instead of completely eliminating HIV, it may be possible to induce a functional remission similar to that seen in successfully treated cancer patients, where the immune system can keep the offending pathogenic activity in check. Lewin reminded the conference that the integrated yet unexpressed HIV-1 DNA in resting, long-lived central memory and slow-proliferating transitional memory CD4+ T cells, among other leukocyte subsets (and indeed, unknown cell reservoirs), prevents highly active antiretroviral therapy (HAART) from completely eliminating HIV-1 from the human body. This section covers highlights from the ‘HIV reservoirs: what are the strategies for elimination?’ talk.
As Tae-Wook Chun (National Institute of Allergy and Infectious Diseases, MA, USA) explained, in vivo antigen-mediated reactivation of CD4+ central memory and transitional memory T cells induces HIV-1 replication: CD4+ T cells are understood to form 95% of the latent cellular reservoir. The precise frequency, however, of the latent reservoir is highly controversial, as noted by Nicholas Chomont (Centre de Recherche du Centre Hospitalier de l’Université de Montréal Saint-Luc, Montréal, Québec, Canada). Chomont also added that frequency and composition of the latent reservoir may possibly show variability across patients.
Several novel strategies to diminish the latent reservoir and induce functional remission were discussed. Chun and Alain Lafeuillade (General Hospital, Toulon, France) suggested a multidrug, multifaceted attack upon latent reservoirs. Most speakers suggested this would involve various strategies, including: early HAART initiation to allow for HIV-specific immunity preservation; HIV-1-specific killing agents (e.g., bryostatin); and cell sabotage with immunomodulators such as IL-7.
Chun observed that latent HIV-1 DNA does not currently decay at a clinically satisfactory rate. Based on several previous studies, Chun observed that initiating HAART earlier may preserve a greater degree of HIV-1-specific immunity. However, Chun reminded the audience of an important caveat: even in patients with intensive HAART-induced low HIV-1 burden, one may still observe rebound. Thus, one cannot say for definite that known latent reservoirs are the only contributors to persistent viral load. Additional research is required to fully define the origin of persistent viremia in well-suppressed patients.
Anatomical viral sanctuaries for HIV-1 within the human body (viral reservoirs sequestered from the immune system or drug penetration in specific tissues, e.g., the CNS) present a further challenge to latent reservoir elimination, as noted by Chun. Lafeuillade’s summation at the end of the session supported the concept that newly developed agents used in the aforementioned multifaceted attack must be able to penetrate numerous anatomical barriers in addition to surpassing the problem of circulating memory CD4+ T cells.
Future attempts to eliminate the HIV-1 latent reservoir may encounter further challenges. The absence of a well-understood common pathway underlying the transition from active CD4+ T cells to resting or slow proliferating subsets presents the largest barrier. In addition, Chun highlighted from previous studies that 8% of the human genome comprises pro-viral DNA from ancient retroviruses, which are regulated by the same mechanisms that modulate HIV-1 replication – if these are inadvertently reactivated by novel therapeutics, one might risk inducing lymphoma.
Novel therapeutic strategies
There are currently 25 US FDA-approved drugs available for use in triple combination HAART. Current HAART drug classes are defined by their ability to inhibit the main protein involved in each key stage of the HIV-1 lifecycle, for example, integrase inhibitors prevent the integration of HIV-1 DNA into the genome by direct action on HIV-1 integrase. Four ongoing drug development trials aiming to move the assault on HIV-1 to novel targets were presented in the ‘Novel therapeutic strategies’ oral abstract session, and are considered below.
Helga Hofmann-Sieber (Heinrich-Pette-Institute for Experimental Virology & Immunology, Hamburg, Germany) presented new data on a different strategy for reducing HIV-1 viral load at the nucleus level. Hofmann-Sieber’s group studied HIV-1 pro-viral excision with various proteins, and presented promising data on tre-recombinase, which they established can recognize 34 asymmetrical sequences in the long-terminal repeat region of the HIV-1 genome. The in vitro arm involved insertion of tre-recombinase vectors into both Jurkat and PM1 CD4 T-cell lines with controls for each cell line. They discovered that tre-recombinase is nontoxic in both Jurkat and PM1 T-cell lines. All T-cell subsets were then infected with CCR5-tropic HIV-1 Bal. Their group demonstrated a significant reduction in measured HIV-1 p24 (core antigen) in treated versus control cells.
Hofmann-Sieber’s in vivo arm involved ‘humanized’ mice (Rag 2-/-γc-/-) that received transfusions of human peripheral blood then either T cells or CD4-expressing hematopoetic stem cells. At a 2-week follow-up, tre-recombinase-treated mice showed a 100% reduction in plasma HIV-1 viral load across both lines. A total of 3 weeks post-HIV-1 administration, Hofmann-Sieber’s group discovered interesting differences in the ratio of receptor expression in the stem cell line – the intervention group showed equal CD4:CD8 receptor expression profiles, while the control group showed CD8 receptor expression predominance yet overall decreased expression of both receptors. Over 15 weeks, no toxicity was observed in their murine model, suggesting short-term adverse effect profiles may be favorable in the human model.
Hofmann-Sieber admitted that their sample size was small, as this was a pilot study. Her group’s further research will involve repeating their original method with an expanded sample population of mice. Hofmann-Sieber’s group plans to consider different types of HIV-1, including those not possessing the ideal tre-recombinase-binding long terminal repeat target sequence.
Mark Underwood (GSK, NC, USA) discussed a new integrase inhibitor candidate, S/GSK1265744. S/GSK1265744 was designed and selected with the objective of achieving bioavailability and potency sufficient for once-daily dosing in raltegravir (a licensed integrase inhibitor) resistant isolates. A total of 39 isolates were examined from patients in the UCSF SCOPE trial cohort. The primary outcome measure was fold change in viral susceptibility (post-intervention viral load divided by preintervention viral load) for raltegravir versus the S/GSK1265744 regimen in a cohort followed over time. In this trial, both groups maintained an optimized background regimen. After approximately 12 months of therapy with S/GSK1265744, Underwood’s group determined that S/GSK1265744 is significant in terms of virological response compared with raltegravir in the integrase inhibitor resistance mutation Q148H isolate group. Underwood’s group also found that in 80% of isolates, HIV-1 was five-times more susceptible to S/GSK1265744 compared with raltegravir alone. Further research by Underwood’s group will involve characterization of secondary mutations.
Frauke Christ (Katholieke Universiteit Leuven, Leuven, Belgium) revealed data supporting her group’s discovery of the first allosteric suppressor of HIV-1 integrase. LEDGFp75 is a rate-limiting cofactor for HIV replication involved in transiently binding integrase to chromatin. Christ explained that LEDGINs are a group of 2-(quinolin-3-yl)acetic acid derivatives that strongly inhibit the interaction between LEDGFp75 and integrase during HIV-1 establishment in the human genome.
Christ and colleagues have also demonstrated LEDGIN activity in primary peripheral blood monocytes and macrophages, and thus they may be promising in patients harboring CCR5-tropic HIV-1 strains. Christ also reported the potential for adjuvant use of LEDGINs with conventional integrase inhibitors: their modeling of candidate LEDGFp75 sites for LEDGIN binding has suggested LEDGINs may have an additive effect of inhibiting the integration stage of the HIV-1 lifecycle. In addition, Christ’s preliminary data suggest noninferiority, if not superiority, of the LEDGINs compared with raltegravir.
Andrea Savarino (Istituto Superiore di Sanità, Rome, Italy) presented a new sabotage strategy to limit the latent reservoir half-life of HIV-1. Auranofin, the gold-based drug already established in rheumatology, is thought to act by inducing oxidative stress via the creation of reactive oxygen species, leading to death of cell mediators of inflammation. Savarino informed the meeting that auranofin also reduces CD28 (a cell surface receptor involved in cell survival) expression in central memory and transitional memory T cells.
Savarino and colleagues tested wild-type simian immunodeficiency virus-positive macaques (SIVmac251); half were randomized to auranofin and intensified background regimen and the other half were randomized to intensified background regimen alone. Savarino’s group observed that auranofin-treated macaques, upon treatment suspension, showed a predicted increase in viral load, followed by a promising significant decrease in viral load and maintenance of high CD4+ T-cell counts. Savarino noted one challenge with auranofin: after approximately 9 months, patients taking auranofin in rheumatological settings develop a level of resistance, and further work is required to determine the impact this would have on latent reservoir pro-viral DNA levels. Nevertheless, the use of gold-based immunomodulators in conjunction with conventional HAART remains promising.
Future perspective
The XVIII International AIDS Society Conference covered multiple aspects of HAART development. This meeting report has focused on two sessions, the first outlining reasons and general principles underlying the inability of HAART to reduce persistent low level HIV-1 viremia; the second evaluating new conventional HAART or adjuvant candidates that may, when used in concert and aggressively, contribute to reductions in active and latent sources of HIV-1 replication. Over the next 5 years, the challenge will be to formulate novel strategies to inhibit HIV-1 proteins involved in promoting or stabilizing the activity of key HIV-1 lifecycle proteins (e.g., integrase), as well as optimize existing therapeutic strategies to control HIV-1 replication and limit the establishment of latent reservoirs of HIV-1 infection.
Acknowledgements
This conference was organized by the International AIDS Society (www.iasociety.org).
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.