Timing of Antiretroviral Therapy Initiation Determines Rectal Natural Killer Cell Populations

Despite antiretroviral therapy (ART), innate and adaptive immunologic damage persists in the periphery and gut. T memory stem cells (Tscm) and natural killer (NK) cells are pivotal for host defense. Tscm are memory cells capable of antigen response and self-renewal, and circulating and gut NK cell populations may facilitate HIV control. The impact of early ART on circulating and gut Tscm and NK cells is unknown. We enrolled participants who initiated ART during acute versus chronic HIV-1 infection versus no ART in chronic infection. We performed flow cytometry to identify NK and Tscm cells in the blood and rectum and polymerase chain reaction to quantify the HIV-1 reservoir in both sites. We used the Mann-Whitney U-test and Spearman correlation coefficients for analysis. Participants who started ART in acute infection had lower rectal CD56^brightCD16^dim cell frequencies than participants who started ART in chronic HIV-1 infection and lower CD56^bright and CD56^brightCD16^- cell frequencies than participants with chronic infection without ART. Higher circulating NK cell, CD56^-CD16^bright, CD56^dim, and CD56^dimCD16^bright frequencies correlated with higher HIV-1 DNA levels in rectal CD4⁺ T cells, whereas higher circulating CD4⁺ T cell counts correlated with higher rectal NK, CD56^brightCD16^dim, and CD56^dimCD16^bright frequencies. Peripheral CD56^brightCD16^- cells were inversely associated with rectal CD56^-CD16^bright cells. Rectal CD8⁺ Tscm frequencies were higher in participants without ART than participants with chronic infection on ART. Timing of ART initiation determines rectal NK cell populations, and ART may influence rectal Tscm populations. Whether the gut reservoir contributes to NK cell activation requires further study.