584 – Depletion of CX3CR1+ Effector CD8 TRM Cells Is Associated With HIV-1 Reservoir in the Colon on ART

Background

The identification of host immune factors involved in the persistence of tissular HIV-1 reservoirs is crucial for the development of remission strategies. The intact HIV-1 reservoir is higher in the colon compared to other intestinal compartments at the chronic stage on ART, which may be related to the local loss of tissular resident memory CD69⁺CD103⁺ CD8⁺ T cells (T_RM).

Methods

Immunologic and virologic analysis of the intestinal mucosa was performed in 42 virologically suppressed people living with HIV-1 (PWH) on ART and 42 uninfected controls (ANRS EP61 GALT study) using colonic endoscopic biopsies. Characterization of the phenotype and function of T cells within the lamina propria was performed by FACS. Total HIV-1 DNA and residual HIV-1 RNA were quantified in gut samples.

Results

Effector CX3CR1⁺ CD8⁺ T cells were globally increased in the colonic mucosa of PWH on ART compared to uninfected controls (median 15.1% [13.4-17.7] of CD3⁺ cells vs. 8.4% [6.2-10.5], respectively; P<0.001), but CD69⁺CD103⁺ T_RM among CX3CR1⁺ CD8⁺ T cells were decreased (median 32.7% [24.5-42.7] of CX3CR1⁺ CD8⁺ vs. 46.3% [36.4-55.3], respectively; P<0.001). The increased proportion of CX3CR1⁺ non-T_RM (CD69^–CD103^–) correlated with total HIV-1 DNA (ρ=0.42 ; P=0.02) and residual HIV-1 RNA (ρ=0.38 ; P=0.02) in the colon, whereas CX3CR1⁺T_RM were associated with lower HIV-1 DNA levels (ρ=-0.41 ; P=0.02). CX3CR1⁺ CD8⁺ T_RM showed a distinct phenotype from non-T_RM with higher expression of CD39, CD101, CD127, and lower expression of CD57, KLRG1, PD-1, TIGIT and TIM-3 (Figure). CX3CR1⁺ CD8⁺ T_RM were predominantly CD27^– effector memory cells (median 60%), whereas non-T_RM were predominantly CD27⁺ cells. CD39, CD101, CD127 expression on CX3CR1⁺ CD8⁺ T_RM all negatively correlated with total HIV-1 DNA in the colon. T_reg frequency was also increased in the colon of PWH, and negatively correlated with CD39 expression on CX3CR1⁺ CD8⁺ T_RM.

Conclusions

Effector CX3CR1⁺ CD69⁺CD103⁺ T_RM CD8⁺ cells are associated with a reduced HIV-1 reservoir in the colon, but appear to be depleted in favor of CX3CR1⁺ CD69^–CD103^– non-T_RM CD8⁺ T cells with a more exhausted (TIGIT⁺TIM-3⁺LAG-3⁺PD-1^hi) and senescent (CD57⁺) phenotype. Increasing cytotoxic effector CD8⁺ T_RM cells may be an axis to reduce the tissular viral reservoir and achieve HIV-1 remission. 

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