Background:  CD4⁺ and CD8⁺ T cell activation levels often remain elevated in individuals on ART initiated during chronic infection. This persistent inflammatory state has been associated with blunted CD4⁺ T cell recovery and early mortality during suppressive ART. The relationship of timing of ART initiation with on-ART levels of inflammation and with the size of the persistent viral reservoir is incompletely understood.

Methods:  Individuals with acute/early HIV infection (<6 months) who started ART early (<6 months after estimated date of HIV infection) vs later (≥2 years) and who maintained ≥2 years of subsequent virologic suppression were identified in the UCSF Options Project. We assessed T cell activation by mulitparameter flow cytometry to detect expression of CD38, HLA-DR, CCR5, PD-1, CD45RA, and CCR7 on CD8⁺ and CD4⁺ T cells. We compared T cell activation during ART between early and later treated groups. At-risk uninfected persons served as additional controls.

Results:  In unadjusted analyses, the later ART group had a higher frequency of activated CD8⁺ T cells on-ART (n = 32, mean 28.8%) compared to the early ART group (n = 34, mean 22.1%, p = 0.009). Similarly, later ART had a higher frequency of activated CD4⁺ T cells than early ART (7.5% vs 5.2%, p = 0.06). Although early ART participants had better on-ART CD8⁺ T cell activation levels, these levels remained elevated compared to HIV^– controls (p = 0.02 and 0.01 for early ART vs HIV^–, and late ART vs HIV^–, respectively). The persistent T cell activation associated with deferred ART was observed in central memory T cell subsets. Deferred therapy was associated with a 4.8-fold higher level of proviral DNA (p = 0.0045) and 3.2 S/Co units higher cell-associated RNA (p = 0.035). The size of the reservoir during ART was associated with the % activated (CD38, HLA-DR, CCR5, PD1) CD4⁺ and CD8⁺ T cells.

Conclusions:  In recently HIV-infected individuals, delaying ART was associated with higher CD4⁺ and CD8⁺ T cell activation levels and larger HIV cellular reservoirs during virologic suppression. This may be partially mediated by the extent of CD4⁺ T cell depletion and/or cumulative exposure to viremia prior to ART initiation. These results, while observational, suggest that ART initiation in the first 6 months of infection may be associated with lower on-therapy T cell activation levels and smaller HIV reservoirs compared with later ART initiation.