365 – Occult CMV Replication Is a Persistent Driver of Effector T-Cell Expansion in PWH on Effective ART

Background

CMV infection is a driver of immune activation and senescence, with greater impact in the setting of HIV-1 co-infection, where it contributes to CD8 T cell expansion and low CD4/CD8 T cell ratios. CMV replication occurs primarily in people with HIV-1 (PWH) with low blood CD4⁺ T cell counts, but occult CMV replication may persist in some tissues due to incomplete CD4⁺ T cell reconstitution on antiretroviral therapy (ART), particularly in the gut, dissociated from restored blood CD4⁺ T cell counts. This occult CMV replication may drive CMV-specific antibodies and effector T cells even in PWH on successful ART.

Methods

In a sub-study of ANRS EP61 GALT, 15 PWH who were also CMV seropositive (CMV⁺), 15 controls without HIV but CMV⁺, 12 PWH without CMV (CMV^–) and 12 double-negative controls were included for FACS immunophenotyping of circulating T cells. CMV viremia was assessed by PCR. Anti-CMV IgG titers were measured as a marker of immune stimulation by CMV.

Results

CMV viremia was negative in all CMV+ subjects. However, CMV⁺ PWH had significantly higher anti-CMV IgG titers than CMV⁺ HIV-negative controls (median 553 [277-933] vs 163 [122-245], P <0.01). While an inverted Vδ₁/Vδ₂ ratio among γδ T cells has been described as a hallmark of PWH, it was found only in CMV⁺ PWH. γδ T cell counts are increased in PWH, with the highest levels in CMV⁺ PWH compared to CMV^– PWH and CMV^– controls (P=0.0.1 and P<0.001, respectively) (Figure). Vδ₁ subset counts and proportions were significantly increased in CMV⁺ PWH compared to other groups. The Vδ₂ subset was not significantly changed in number, but was reduced in proportion. The effector cell receptor CX3CR1 was highly expressed on Vδ1 T cells, with the highest expression in CMV⁺ PWH. Conventional T cells showed the same results, with an expansion of CX3CR1⁺ TEMRA T cells in the same groups. CMV IgG titers correlated with CX3CR1⁺ CD8 and CD8 TEMRA, total CD8 count, and with the duration of HIV virological suppression.

Conclusions

Occult CMV replication during HIV-1 infection is involved in the expansion of several circulating T cell populations, particularly Vδ₁ T cells, even in PWH on effective ART with restored circulating CD4 T cell counts and undetectable CMV DNA in their blood. CX3CR1 expression on T cells is associated with CMV status and is likely driven by occult CMV replication. CMV IgG titers may be used as a surrogate for occult CMV replication.

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