Dr Santiago Moreno Interview: lessons learned from 2013 CROI
Dr. Santiago Moreno is the Chief of the Department of Infectious Diseases at the Hospital Ramón y Cajal, in Madrid, and Professor of Infectious Diseases at the University of Alcalá de Henares, in Madrid. He has been involved with HIV-infected patients since the very beginning of the AIDS epidemic in Spain. His main research areas of interest include antiretroviral therapy, HIV-related tuberculosis, and HIV cure/eradication. We thank Dr Moreno (and Dr José Alcami who reviewed the text) for having accepted to answer 3 questions.
Alain Lafeuillade: What were the novelties in the nature of HIV reservoirs?
Santiago Moreno: Three different groups have presented evidence that, in addition to the well known memory CD4+ T cells, other cells might constitute important HIV reservoirs: stem cell memory, gamma-delta lymphocytes, and follicular helper T cells. The stem cell memory (abstract 44) represents a minor compartment (only 8% of the total reservoir), but its relevance derives from the fact that it could generate infected central memory T cells by homeostatic proliferation. Gamma-delta lymphocytes (abstract 46) represent a first line barrier against viral infections, and, despite not expressing CD4, they are infected in a high proportion during acute infection. Follicular helper T cells, that collaborate with B lymphocytes in cell differentiation and antibody maturation, have been confirmed as highly susceptible to the in vitro infection with HIV, both R5 and X4, and are infected in vivo during the viremic phases of the infection (abstracts 203 and 252).
AL: What were the novelties on the size and the methods of measurement of HIV reservoirs?
SM: The limitations of the current methods to quantify the HIV reservoir are well known. While the coculture with limiting dilutions underestimates the size of the reservoir, the quantitation of integrated DNA overestimates it with a difference between the two methods of up to 300 fold. The difference was addressed in detail by Ya-Chi Ho (abstract 43) who showed that most of the integrated virus are not replication competent due to important deletions (50%), hypermutations secondary to APOBEC3G (27%), and other mutations (10%). Overall, it is estimated that only 12% of all integrated virus can replicate. Of even more concern is the observation that this population of virus cannot be reactivated despite using potent stimuli such as PHA. The observation was confirmed by another group (abstract 371), showing that only a partial reactivation was achieved with a combination of anti-CD3 and anti-CD28 antibodies. These findings represent an enormous, additional obstacle for the eradication of HIV, and suggest that the mechanisms of maintenance of latency are multiple and different strategies may be needed to reactivate the different integrated viruses.
AL: What were the novelties on eradication trials?
SM: A number of presentations have brought some light on the use of different strategies to decrease the size of the HIV reservoirs: the use of anti-latency drugs, the role of intensification of antiretroviral therapy, and the treatment at very early stages of infection.
A multiple dose clinical trial with vorinostat was presented by Dr. S. Lewin (abstract 50LB), showing that, while the drug is safe, it induces only modest increases in the cell-associated RNA with no increase in plasma viremia. Two additional presentations (abstracts 371 and 376) confirmed the limited reactivating capacity of vorinostat and romidepsin, another HDAC inhibitor. Siliciano’s group has insisted in questioning the efficacy of using only anti-latency drugs to eradicate HIV. They have previously shown that, despite the reactivation of latent HIV, infected cells are not destroyed and, thus, the size of the HIV reservoir remains unchanged, so, they propose the combination of anti-latency drugs with therapeutic vaccines to achieve eradication. Moreover, in a mathematical model, they estimate that decreasing the size of the reservoir by 2, 3 or 4 logs would delay the rebound of viremia during 100, 1,000, and 10,000 days, respectively, after discontinuation of treatment (abstract 386). So, only drugs that can reduce the reservoir at least 3 logs will be clinically useful.
The role of intensification was re-examined in a new clinical trial using raltegravir (abstract 42). The results are superimposable to those obtained by Buzon et al (Nat Med, 2009) showing the increase in 2LTR circles early after intensifying ART, and thus pointing to the persistence of residual replication. The ERAMUNE 01 trial, on the other hand, showed the failure of immunodulators to decrease the reservoir. In this trial, patients were randomized to intensify their suppressive ART with raltegravir and maraviroc or raltegravir, maraviroc and IL-7. IL-7 increased the CD4 count but also increased the size of the reservoir in central memory T cells.
Finally, three papers examined the impact of early antiretroviral therapy on the reservoirs. In a paper from Thailand (abstract 47), ART was initiated in 75 patients with acute infection (Fiebig I to III). A decrease in the proviral DNA was observed in the three groups although the impact was greater in patients in Fiebig I stage. The other two papers showed the effect of early treatment in babies born to HIV-infected mothers (abstract 48LB and 171LB) (see the commentary by Dr. D Persaud on this website).
Abstract 42. Hatano H et al. Increase in 2LTR Circles after Raltegravir Intensification in HAART-suppressed Patients with High CD4+T Cell Counts: A Randomized, Controlled Trial
Abstract 43. Ho YCh et al Characterization of Non-induced HIV1 Proviruses Dampens the Hope for HIV-1 Eradication
Abstract 44. Buzón M. T Memory Stem Cells Are a Long-term Reservoir for HIV-1
Abstract 46. Soriano-Sarabia N et al. Study of Transitional Memory CD4+ T Cells and gammadelta T Cells as Latent Reservoirs for Replication Competent HIV-1
Abstract 47. Ananworanich J et al. Early ART Intervention Restricts the Seeding of the HIV Reservoir in Long-lived Central Memory CD4 T Cells
Abstract 48LB. Persaud D et al. Functional HIV Cure after Very Early ART of an Infected Infant
Abstract 50LB. Elliot J et al. The Safety and Effect of Multiple Doses of Vorinostat on HIV Transcription in HIV+ Patients Receiving cART
Abstract 170aLB. Katlama C et al. Impact of Interleukin-7 and Raltegravir+Maraviroc Intensification on Total HIV DNA Reservoir: Results from ERAMUNE 01.
Key words: ERAMUNE, HDAC inhibitors, HIV cure, HIV eradication, HIV latency, HIV reservoirs, HIV workshop, Interleukin-7, vorinostat