Study Examines Mechanisms of Rare Paradoxical Response to ART in HIV


In rare cases, patients with HIV can experience a paradoxical response to antiretroviral therapy known as extreme immune decline.

In most individuals with HIV, antiretroviral therapy (ART) can successfully suppress HIV-1 replication and reconstitute CD4+ T cells. However, in rare cases, a paradoxical response to ART called extreme immune decline (EXID) can occur, according to a new report published by JCI Insight.

For the study, EXID was defined as a progressive and persistent decrease in CD4+ T cell counts despite 192 weeks of ART, in the absence of malignancy and regardless of pre-ART CD4+ T cell counts. The researchers reported on 5 patients evaluated at the National Institute of Allergy and Infectious Disease who experienced a significant decline in CD4+ T cell level despite suppression of HIV below detectable levels for more than 3 years.

The researchers compared the effect of EXID with individuals defined as immunological non-responders (INRs) who respond inadequately to ART. According to the study, the researchers found that the immune systems of patients with EXID fared worse than INRs. INR patients who consistently received ART for 4 years had CD4+ T cell counts that increased on average by 193 cells per microliter of blood.

Comparatively, individuals who respond normally to ART increased their CD4+ T cell count by more than twice that amount. However, patients with EXID experienced an average decline of 157 CD4+ T cells per microliter while consistently maintaining viral suppression on ART, according to the study.

Based on the analysis, the researchers found that genes influencing immune cell activity and autoimmunity may play a role in EXID, but noted there does not appear to be a single cause. Additionally, all of the patients in the study with EXID had HIV strains other than clade B HIV, suggesting that certain combinations of genes and the HIV strain may be associated with EXID as well.

“A comprehensive prospective clinical, immunological, and genetic characterization of these patients led to the identification of what we believe are novel mechanisms causing CD4+ T cell depletion in ART-treated individuals, specifically autoimmunity and inflammasome/caspase-1 activation,” the researchers wrote in the study.

Although EXID is a rare occurrence, the researchers concluded that studying these rare exceptions can provide insight into the specific mechanisms of HIV and the immune system.


Lisco A, Wong CS, Lage SL, et al. Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression. JCI Insight. 2019. Doi: 10.1172/jci.insight.127113

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