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In Small Amount of Patients, CD4+ T Cells Continue to Decline Despite Being Virally Suppressed


In rare cases, despite being on antiretroviral therapy and being virally suppressed, patients experience extreme immune decline.

Adherence to antiretroviral therapy (ART) allows patients with HIV to become virally suppressed, and with that typically comes restoration of CD4+ T cells, which improves immune function and health outcomes. However, in rare cases, patients have a paradoxical response to ART, according to new study findings.

In these patients, their CD4+ T cells actually continue to decline despite being virally suppressed and changing ART regimens. This response, known as extreme immune decline (EXID), is distinct from immunological nonresponse, in which patients achieve just a modest increase of CD4+ T cells while taking ART.

“EXID was not associated with previously described predictors of poor immune response, as it occurred in young individuals, with higher nadir CD4+ and without any consistent increase in cycling CD4+ T cells or activated CD4+ or CD8+ T cells,” wrote the researchers.

The researchers found that among 5 patients with non-B HIV-1 subtypes referred to the National Institutes of Health Clinical Center for EXID, there was a median CD4+ T cell count of 179 cells/mcL before ART, which dropped significantly to 36 cells/mcL after 192 weeks of ART and consistent viral suppression.

In addition to faring worse than patients who had an immunological response, patients with EXID also had worse outcomes when compared with the immunological nonresponders (INRs). While EXID patients lost an average of 157 cells/mcL between baseline and week 192, the 15 INRs gained an average of 193 cells/mcL and the 8 immune responders gained an average of 427 cells/mcL during the time period.

Despite the long-term follow-up, with a small sample size and observed differences in immunological correlates due to differences in mechanisms underlying EXID, the researchers were unable to generalize findings. However, they did come away with 2 mechanisms that contributed to the CD4+ T cell depletion in these patients.

“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,” wrote the researchers.

Among the patients, 2 produced antibodies that attacked their own T cells and 2 had overactive immune responses, which led to increased inflammation.


Lisco A, Wong CS, Lage S, et al. Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression [published online April 18, 2019]. JCI Insight. doi: 10.1172/jci.insight.127113.

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