Immunodiscordant responses to HAART – mechanisms and consequences

Abstract

A relevant fraction of HIV-1-infected individuals (ranging from 15 to 30%) presenting virologically successful highly active antiretroviral therapy fail to recover CD4 T-cell counts. These individuals, called immunodiscordant or immunological nonresponders, are at increased risk of clinical progression and death. Although older age, lower nadir CD4 T-cell count and HCV co-infection are some of clinical predictive factors, immunological mechanisms rely on impaired thymic production and accumulation of apoptosis-prone CD4 T cells. Indeed, immunodiscordant individuals may show increased tissue fibrosis and damage of gut-associated lymphoid tissue that results in higher hyperactivation, inflammation and immunosenescence, altered Treg/Th17 ratio and increased T-cell death. A better knowledge of the final pathogenic mechanism and factors influencing CD4 T-cell recovery will help to select the optimal therapeutic strategies for them.

Keywords::

• apoptosis
• CD38
• CD57
• cell death
• immunosenescence
• naïve T cells
• T-cell differentiation

Financial & competing interests disclosure

Work in IrsiCaixa is supported by the European Union's Seventh Framework Programme (NEAT Project); the Spanish Ministry of Science and Innovation (PI11/02098, Red de Investigación en SIDA RIS, RETICS12/0014), the Catalan HIV Vaccine Development Program (HIVACAT), ‘Gala contra la SIDA’ Barcelona 2012 and ‘Les Nostres Cançons contra la SIDA’ Barcelona 2012. E Negredo has received research funding, consultancy fees or lecture sponsorships from GlaxoSmithKline, ViiV, Merck and Roche. B Clotet has served as a consultant on advisory boards or participated in speakers’ bureaus or conducted clinical trials with Boehringer-Ingelheim, GlaxoSmith-Kline, Gilead, Janssen, Merck, Pfizer and ViiV. J Blanco has received research funding, consultancy fees or lecture sponsorships from GlaxoSmithKline, ViiV and Merck. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Up to 30% of treated HIV-1-infected individuals fail to recover properly CD4 T cells.

• • Immunodiscordance response to HAART is associated with an increased risk of clinical progression (AIDS and non-AIDS related) and death.

• • Late diagnosis of HIV-1 infection and the accumulated HIV-induced lymphoid tissue damage (including gut-associated lymphoid tissue) may account for poor CD4 T-cell recovery.

• • Residual viral replication is not a major cause of poor CD4 T-cell recovery as demonstrated by several intensification studies.

• • A definition of the main immunological force behind immunodiscordance is required for proper treatment, impaired T-cell production or limited CD4 T-cell lifespan/increased destruction.

• • Different subgroups of immunodiscordant individuals may exist, which could be defined by the role played by genetic background, ART toxicity or co-infections.

• • Is there a major (targetable) cause of persistent immune activation and increased cell death in immunodiscordant patients?

• • Is immunodiscordance irreversible?