HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality

Abstract

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28− and CD57+CD28−), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

“…Our data interconnect recent findings regarding the higher risk of morbidity and mortality associated with both low-CD4-recovery subjects (1, 2) and low-CD4/CD8-Tcell-ratio subjects (7,8). More importantly, although the CD8 T-cell pool has not been classically considered relevant in this scenario, our data suggest that homeostasis of the CD8 T-cell pool, probably interacts with the homeostasis of CD4 T cells, also contributing to this scenario.…”

“…The HIV infection leads to an inversion of the CD4/CD8 T-cell ratio (7), and globally, the CD4/CD8 T-cell ratio has been associated with clinical progression, independently of CD4 counts (7)(8)(9). However, whereas a low baseline CD4 count is undoubtedly associated with immunodiscordance, a potential different meaning of the baseline CD4/CD8 T-cell ratio has not yet been explored.…”

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

“…CD8 + T-cell persistence in treated HIV-infected donors contributes to abnormally low ratios of CD4 + T cells to CD8 + T cells (hereafter, "CD4 + /CD8 + ratios"), now recognized as associated with a greater risk for morbidity, including cardiovascular events [2][3][4][5]. A relationship to vascular health is suggested by observations that an inverted CD4 + /CD8 + ratio is also associated with greater intima media thickness and arterial stiffness, both of which are important predictors of cardiovascular morbidity [4,6].…”

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection

“…Depleted response from EBV-and HHV-8-specific CD8 cytotoxic cells may facilitate carcinogenesis among immunocompromised hosts [36]. The extent to which the normalization of the CD4:CD8 ratio following cART initiation reflects a recovery of CD8 cell response is unclear [37], but this may explain why adjustment by CD4:CD8 partially attenuated the benefit of immediate cART in reducing cancer risk.…”