Timing of Antiretroviral Therapy Initiation Determines Rectal Natural Killer Cell Populations

Abstract

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 bright CD16 dim cell frequencies than participants who started ART in chronic HIV-1 infection and lower CD56 bright and CD56 bright CD16cell frequencies than participants with chronic infection without ART. Higher circulating NK cell, CD56-CD16 bright , CD56 dim , and CD56 dim CD16 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 bright CD16 dim , and CD56 dim CD16 bright frequencies. Peripheral CD56 bright CD16cells 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.

Natural killer cells during acute HIV-1 infection: clues for HIV-1 prevention and therapy

“…Although these data are limited by the sample size, they suggest a role for NK cell responses in shaping the viral reservoir in neonates [77]. This notion is further supported by another study in adults in whom a correlation between frequency of circulating CD56 − CD16 bright and CD56 dim NK cells and the level of HIV-1 DNA in rectal CD4 + T cells has been demonstrated [75]. Notably rectal NK cell subsets differed depending on whether ART was initiated during acute or chronic infection [75].…”

“…Although antiretroviral therapy (ART) introduction mitigates some defects in the NK cell compartment, altered NK cell subset re-distribution and impaired functionality persist despite successful virological suppression [69][70][71][72]. Data from NHP early treatment models and limited evidence from ART initiation studies during acute infection suggest that the trajectory of HIV-related inflammation and the degree of functional restoration may vary with the timing of ART initiation [73][74][75].…”

“…Profiling of circulating NK cells in individuals treated during AHI has shown that early ART administration partially restricts NK cell redistribution by moderating CD56 bright NK cell depletion [49,75,76]. An in-depth longitudinal study of immediate ART initiation in a cohort of neonates with HIV-1 infection who initiated ART shortly after birth (EIT), compared with infants treated during the first year, showed that EIT infants display a distinct NK cell profile [77].…”

Clearance of HIV infection by selective elimination of host cells capable of producing HIV

“…mRNA was extracted and converted to cDNA using the SuperScript VILO cDNA Synthesis Kit (Thermo Fisher Scientific), followed by real-time PCR for Pol-1 and LTR-gag as above. Quantity of viral DNA was performed by real-time PCR of genomic DNA from the cells with the described primers as described 68 : forward primer, 5′-GGTCTCTCTGGTTAGACCAGAT-3′ and reverse primer, AGATTTTCCACACTG and probe 5′-6FAMAGTAGTGTGTGCCCGTCTGTT-TAMRA-3′) for amplification of an HIV-1 LTR sequence.…”

Immunotherapeutic Potential of T Memory Stem Cells

“…During HIV infection, T cells play an important role in controlling virus replication. In patients receiving inhibitory antiretroviral therapy, CD8 + T SCM with stem cell characteristics was found to be more abundant than untreated patients (154). In addition, prolonging the treatment time can increase the ratio of CD8 + T SCM , and preferentially secrete IL-2 under viral stimulation, indicating that CD8 + T SCM is an important part of the cellular immune response to HIV-1.…”