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Poor CD4 Response Despite Undetectable Load Marked by Vascular and T-Cell Dysfunction
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
People whose CD4 count remained below 350 despite attaining a viral load below 50 copies had worse flow-mediated vasodilation and T-cell function than people whose CD4 count climbed above 350 [1]. Researchers from the University of California, San Francisco (UCSF) believe the immunologic abnormalities detected are "consistent with premature immunologic aging and immunosenescence."
The study involved 360 members of the UCSF SCOPE cohort, all with durable viral load suppression; 111 study participants had a "low" CD4 count that stayed under 350, while the count climbed above 350 in 249 people in the "high" CD4 group. The UCSF team tracked viral loads with an ultrasensitive assay. In a subset of patients, the investigators assessed markers of T-cell activation and maturation, and they measured flow-mediated vasodilation of the brachial artery, a predictor of cardiovascular disease.
Median CD4 count stood at 188 in low-CD4 group and at 436 in the high group (P < 0.0001). The low-CD4 group was significantly older (49 versus 45, P = 0.0001), had a higher proportion of men (93% versus 83%, P = 0.009), and had a lower nadir CD4 count (60 versus 166, P < 0.0001). Duration of suppressive antiretroviral therapy was significantly shorter in the low-CD4 group (median 15 versus 36 months, P = 0.002).
Low-level plasma viremia tended to be higher in the low-CD4 group, 3.39 versus 0 copies, P = 0.09). Poor CD4 responders had a significantly higher proportion of activated or dysfunctional CD4 cells, measured as CD38+ HLA-DR+ CD4s (P = 0.0001), CD38+ HLA-DR+ CCR5+ PD1+ CD4s (P < 0.0001), and PD1+ CD4s (P < 0.0001). Frequency of activated central memory cells was also significantly higher in the low-CD4 group, reflected in calculation of three marker sets: CD45RA-CCR7+ CD38+ HLA-DR+ CD4s (P = 0.0002), CD45RA-CCR7+ CD38+ HLA-DR+ CCR5+ PD1+ CD4s (P = 0.0001), and CD45RA-CCR7+ PD1+ CD4s (P < 0.0001).
Poor CD4 responders had significantly higher frequencies of cytomegalovirus-specific and HIV gag-specific CD4 cells (P < 0.01). Cell-associated HIV RNA was significantly lower in the low-CD4 group (P < 0.0001). And flow-mediated vasodilation of the brachial artery was significantly lower in the low-CD4 group (3.18% versus 4.07%, P = 0.05).
The UCSF investigators suggested their findings imply that "a link between 'immunologic failure' . . . and the risk of non-AIDS morbidity may be mediated in part by T cell activation, T cell dysfunction, and/or vascular dysfunction." They proposed that "targeted interventions with immune-based therapeutics will likely be necessary to establish the causal pathways for these associations."
Reference
1. Hatano H, Hsue P, Hunt P, et al. Low CD4 Count on effective HAART is associated with immunologic and vascular dysfunction. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 540.
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