P16-21. Altered T cell homeostasis and activation in HIV-1 elite suppressors with low CD4+ T-cell counts

Background

HIV-1 elite-suppressors (ES) maintain low viral-load (VL) without therapy and classically maintain normal CD4⁺counts. We have identified a rare subset with falling CD4⁺counts (discord-ES). Disease progression in these patients may result from a viral influence on T-cell homeostasis and activation, rather than a direct consequence of virus-replication. Therefore, we compared T-cell homeostatsis and activation in discord-ES and typical-ES.

Methods

Fresh whole blood samples were obtained from 8 discord-ES (VL<2000 copies/ml >1 year, CD4⁺count <450 × 10⁶/L), 12 typical-ES (VL<2000 copies/ml >1 year, CD4⁺count >450 × 10⁶/L), 5 progressors (VL>5000 copies/ml, CD4⁺count <450 × 10⁶/L) and 5 uninfected individuals. Using multiparameter flow-cytometry we quantified naïve and memory T-cell subsets based on expression of CD45RA/RO and CD62L, and assessed activation based on co-expression of CD38 and HLA-DR.

Results

Blood from discord-ES contained fewer naïve (CD45RA⁺62L⁺) CD4⁺ T-cells than blood from typical-ES (median 80[IQR 52–121] versus 277[218–401]; p = 0.001). This lower number of naive T-cells represented a lower proportion of total CD4⁺ T-cells. Numbers of naive CD4⁺ T-cells in discord-ES did not differ significantly from those in progressors and were reduced (p = 0.002) compared with uninfected controls. A similar pattern was observed with regard to numbers of CD4⁺ central-memory (CD45RO⁺CD62L⁺) and effector-memory (CD45RO⁺CD62L^-) populations. Both activated and resting naive CD4⁺ T-cells were reduced in number in discord-ES, but activated cells constituted an increased proportion of the naive CD4⁺ pool compared with typical-ES (p = 0.003).

Conclusion

CD4⁺ T-cell subsets and their activation in discord-ES are distinct from those in typical-ES and indistinguishable from those in progressors, suggesting that CD4⁺ T-cell decline is more closely associated with perturbations in T-cell activation than with VL. The increased proportion of activated naïve CD4⁺ T-cells against a backdrop of declining numbers of these cells in discord-ES may suggest that activation contributes to progressive cell-loss despite only low-level viral-replication. However, impaired T-cell production or sequestration to non-blood compartments may also contribute.