Antiretroviral therapy (ART) is highly effective at controlling HIV infection, but a cure remains difficult to achieve due to the persistence of a small viral reservoir in blood and tissues. This reservoir is not targeted by ART and can reignite infection if treatment is stopped. Reducing or removing this reservoir is essential for achieving an HIV cure.

Starting ART during early HIV infection is known to result in a smaller viral reservoir compared to starting during chronic infection. However, until now, it was unclear whether early ART has lasting effects on the reservoir if therapy is interrupted and restarted years later during chronic infection.

Recent research by scientists from the Amsterdam institute for Immunology and Infectious diseases (AI&I) published in Nature Communications has revealed that temporary ART, when initiated during early HIV infection, has a long-term suppressive effect on the viral reservoir, as observed when therapy is restarted after several years. This represents a novel effect of early ART on the viral reservoir. Notably, the study also found no detrimental effect of a long treatment interruption on the HIV reservoir. These findings are particularly relevant for the design of HIV curative interventions that require a treatment interruption.

Research approach and collaborations

The study, led by Dr. Alexander Pasternak (Laboratory of Experimental Virology, Amsterdam UMC, location AMC), examined a cohort of people with HIV who received temporary ART during early infection as part of the Primo-SHM clinical trial The research was made possible through collaborations with Prof. Jan Prins, who led the Primo-SHM trial, as well as with Dr. Godelieve de Bree and Prof. Neeltje Kootstra. Pien van Paassen, an AI&I PhD candidate, performed the immunological analyses.

HIV reservoir and immunological parameters were measured in participants of the Primo-SHM trial, a randomized controlled trial comparing no treatment with 24 or 60 weeks of temporary ART initiated during early infection. All participants (re)started ART during chronic HIV infection after a median of 2.5 years without treatment, providing a unique opportunity to quantify the viral reservoir during both therapy periods. This is the only study of its kind with longitudinal samples collected during both early and chronic therapy periods, offering unprecedented insight into the long-term effects of early ART.

Remarkably, among participants who had received ART during early infection, there was no significant difference in the HIV reservoir size between early and chronic ART periods, indicating that even a long-term treatment interruption does not irreversibly alter the reservoir if ART is started early. Furthermore, the HIV reservoir during chronic infection ART was significantly lower in those who had been pre-treated during early infection compared to those who had not. These results indicate that temporary early ART has a lasting suppressive effect on the viral reservoir, as revealed during therapy reinitiation after several years. Moreover, HIV reservoir size negatively correlated with HIV-specific immune responses during therapy, suggesting that HIV-specific immunity may restrict the HIV reservoir on ART.

Practical implications

This study uncovers a novel, suppressive effect of temporary early ART on the HIV reservoir, which is important for clinical decision-making. In particular, the finding that a long treatment interruption does not irreversibly change the reservoir is highly relevant for the design of HIV curative interventions that require a treatment interruption. These results may help inform and optimize current curative strategies.

‘Besides its effect on the HIV reservoir, temporary early ART also lowers the viral setpoint after therapy interruption. We are interested to explore the viral mechanisms behind these effects. In particular, we are studying the effect of temporary early ART on viral diversity and evolution following treatment interruption’.
Dr. Alexander Pasternak
Senior researcher at the Department of Medical Microbiology (Laboratory of Experimental Virology).

For more information contact Alexander Pasternak (a.o.pasternak@amsterdamumc.nl) or read the scientific publication below:

Text: Esmée Vesseur and Alexander Pasternak

Amsterdam UMC researchers involved:

Alexander Pasternak1, PhD, Senior researcher

Pien van Paassen1, MD, PhD-candidate

Yara Verschoor, Research intern (Feb 2016 – Jul 2016)

Jelmer Vroom, Virological analyst (Feb 2016 – Jun 2016)

Karel van Dort1,2, BEng, Research analyst

Irma Maurer, Research technician

Marlous Grijsen, PhD, PhD Fellow (Jul 2008 – Jun 2012)

Ferdinand Wit1,3, PhD, Senior researcher

Godelieve de Bree1,2, PhD, Principal investigator

Neeltje Kootstra1,2, Professor of Immune Pathogenesis of Viral Infections and Interventions

Jan Prins1, Professor of Internal Medicine

Ben Berkhout1, Professor of Human Retrovirology

1Amsterdam Institute for Immunology and Infectious diseases (AI&I), Amsterdam UMC, the Netherlands

2Amsterdam Public Health, Amsterdam UMC, the Netherlands

3Stichting hiv monitoring, Amsterdam, the Netherlands

Funding

This study was supported by Aidsfonds Netherlands under grant number 2011020 to Alexander Pasternak.

Learn more about HIV Vaccine research at the Amsterdam institute for Immunology and Infectious diseases:

Acknowledgement image: Imperial Medicine Blog, article ‘HIV antiretroviral therapy: 'Getting to the heart of the matter’ by Akif Khawaja.