Abstract
HIV-1 infection expands large populations of late-stage differentiated CD8 T cells that may persist long after viral escape from TCR recognition. In this study, we investigated whether such CD8 T cell populations can perform unconventional innate-like antiviral effector functions. Chronic untreated HIV-1 infection was associated with elevated numbers of CD45RA+CD57+ terminal effector CD8 T cells expressing FcγRIIIA (CD16). The FcγRIIIA+ CD8 T cells displayed a distinctive transcriptional profile between conventional CD8 T cells and NK cells, characterized by high levels of IKZF2 and low expression of IL7R This transcriptional profile translated into a distinct NKp80+ IL-7Rα- surface phenotype with high expression of the Helios transcription factor. Interestingly, the FcγRIIIA+ CD8 T cells mediated HIV-specific Ab-dependent cellular cytotoxicity (ADCC) activity at levels comparable with NK cells on a per cell basis. The FcγRIIIA+ CD8 T cells were highly activated in a manner that correlated positively with expansion of the CD8 T cell compartment and with plasma levels of soluble mediators of antiviral immunity and inflammation such as IP-10, TNF, IL-6, and TNFRII. The frequency of FcγRIIIA+ CD8 T cells persisted as patients initiated suppressive antiretroviral therapy, although their activation levels declined. These data indicate that terminally differentiated effector CD8 T cells acquire enhanced innate cell-like characteristics during chronic viral infection and suggest that HIV-specific ADCC is a function CD8 T cells use to target HIV-infected cells. Furthermore, as the FcγRIIIA+ CD8 T cells persist in treatment, they contribute significantly to the ADCC-capable effector cell pool in patients on antiretroviral therapy.
Highlights
ITKerZmFi2n+alILE-f7feRc−toTrrCaDns8crTipCtieollnsaDl Sefiignneadtubryean Express Fc γRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity
There was no significant difference in FcgRIIIA expression levels on FcgRIIIA+ CD8 T cells between HIV-1–infected and uninfected participants
To address the stability of the FcgRIIIA+ CD8 T cell pool over time, we studied a second cohort of Ugandan HIV-1–infected subjects (n = 32) located in Kampala, where longitudinal samples were available from before and after initiation of antiretroviral therapy (ART) (Table I)
Summary
Study participants aged 15–49 y were enrolled in a prospective community-based cohort to assess the prevalence and incidence of HIV-1 infection in Rakai District, Uganda, from 1998 to 2004 (Table I) [41,42,43]. HIV-1 testing was performed as described previously [43]. Positive samples were subjected to the Amplicor HIV-1 Monitor test, version 1.5 (Roche Diagnostics, Indianapolis, IN). The HIV-1–infected study participants initiating ART were from the Couples Observation Study (COS) in Kampala Uganda as previously described [45]. The index partner in each HIV-1–serodiscordant couple was followed up after the initiation of ART. Samples were collected; CD4 T cell counts determined and viral load assessments made at baseline, 6 and 12 mo after initiation of ART
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