IMPORTANCE In individuals with human immunodeficiency virus 1 (HIV-1) contamination who also are receiving antiretroviral therapy (ART) factors that promote full immune recovery are not well characterized. to hepatitis B computer virus (HBV) vaccine an indication of in vivo immune function were PF 670462 also assessed. The timing of ART was indexed to the EDS and/or access into the cohort. The CD4+ counts in HIV-1-uninfected PF 670462 populations were surveyed. MAIN OUTCOMES AND Steps Normalization of CD4+ counts to 900 cells/μL or higher AIDS development HBV vaccine response as well as T-cell activation dysfunction and responsiveness. RESULTS The median CD4+ count in HIV-1-uninfected populations was approximately 900 cells/μL. Among 1119 HIV-1-infected participants CD4+ normalization was achieved in 38.4% vs 28.3% of those initiating ART PF 670462 within 12 months vs after 12 months from your EDS (= .001). Incrementally Mouse monoclonal to STAT5B higher CD4+ recovery (<500 500 and ≥900 cells/μL) was associated with stepwise decreases in AIDS risk and reversion of markers of immune activation dysfunction and responsiveness to levels approximating those found in HIV-1-uninfected persons. Participants with CD4+ counts of 500 cells/μL or higher at study access (adjusted odds ratio [aOR] 2 95 CI 1.51 < .001) or ART initiation (aOR 4.08 95 CI 3.14 < .001) had significantly increased CD4+ normalization rates compared with other participants. However even among individuals with a CD4+ count of 500 cells/μL or higher at both study access and before ART the odds of CD4+ normalization were 80% lower in those initiating ART after 12 months from your EDS and study access (aOR 0.2 95 CI 0.07 = 001). Initiation of ART within 12 months of EDS vs later was associated with a significantly lower risk of AIDS (7.8% vs 15.3%; = .002) reduced T-cell activation (percent CD4+HLA-DR+ effector memory T cells 12 vs 15.6%; = .03) and increased responsiveness to HBV vaccine (67.9% vs 50.9%; = .07). CONCLUSIONS AND RELEVANCE Deferral of ART beyond 12 months of the EDS diminishes the likelihood of restoring immunologic health in HIV-1-infected individuals. The goal of antiretroviral therapy (ART) in patients with human immunodeficiency computer virus-1 (HIV-1) contamination has focused primarily on achieving an undetectable plasma HIV viral weight (VL) because failure to achieve this virologic landmark is usually associated with highly impaired immune recovery.1-3 Durable VL suppression is usually readily attainable with potent and well-tolerated ART shifting attention to the goal of optimal reconstitution of a severely compromised immune system which is the central pathogenic feature of HIV infection.1 4 However a specific CD4+ T-cell count as a target for optimal immunologic health has not been validated nor has an interval from infection to ART initiation that promotes this goal been established. In clinical practice an increase in the CD4+ count to 500 cells/μL or higher while receiving ART is typically regarded as optimal immune recovery.2 8 However our group11 previously showed that in individuals without HIV infection the median CD4+ count is approximately 900 cells/μL. This observation raised the possibility that HIV-infected persons with CD4+ counts less than 900 cells/μL while receiving VL-suppressive ART may remain immunologically compromised. Substantiating this obtaining individuals with CD4+ counts between 500 and 750 cells/μL who are receiving ART have an increased risk of AIDS compared with those having higher CD4+ counts.12 In the present study we tested the hypothesis that normalization of CD4+ counts (≥900 cells/μL) compared with attainment of lower CD4+ counts during VL-suppressive ART is associated with (1) mitigated AIDS risk; (2) reduced T-cell activation and exhaustion which are factors predictive of adverse clinical outcomes (death AIDS and non-AIDS comorbidities)1 12 and (3) enhanced T-cell responsiveness to T-cell trophic cytokines such as interleukin 7 (IL-7) a key player in T-cell homeostasis.15 We tested our hypothesis in the US Military HIV Natural History Study (NHS) a large observational cohort of individuals with HIV infection in which most participants have estimated dates of seroconversion (EDS).16-19 The results of the study in the NHS cohort affirmed our hypothesis prompting us to identify actionable items that physicians and public health policymakers could undertake to facilitate and promote CD4+ normalization. Earlier vs later ART is usually traditionally defined by whether ART is initiated before or after CD4+ counts have declined below a specific threshold (eg 500 cells/μL) rather than the period of HIV contamination before initiation of ART.2 3 20 21 However our group’s11. PF 670462