Short Communication: Expression of Host Restriction Factors by Memory CD4+ T Cells Differs Between Healthy Donors and HIV-1-Infected Individuals with Effective Antiretroviral Therapy

Abstract

Much has been learnt from the functions of host restriction factors during acute and chronic HIV-1 infection, but far less is known about their role in HIV-1-infected individuals in which viral load is stably suppressed with antiretroviral therapy (ART). In this study transcriptional expression of 42 host restriction factors was determined for memory CD4+ T cells sorted from 10 uninfected and 21 HIV-1-infected individuals, treated with suppressive ART and for which the viral reservoir was quantified. No significant associations were observed between restriction factor expression and HIV-1 reservoir size, quantified by measurement of HIV-1 Gag DNA using droplet digital polymerase chain reaction, and by measurement of replication-competent inducible virus using quantitative viral outgrowth assays. Expression of eight of the restriction factors differed significantly, and with a false discovery rate of <10%, between ART-suppressed and uninfected individuals. APOBEC3G, ISG15, LGALS3BP, RNASEL, and MX2 were upregulated in the ART-suppressed individuals, likely because of increased levels of immune activation observed in virally suppressed compared with uninfected individuals. In contrast CDKN1A, TRIM11, and BRD4 were expressed at lower levels in ART-suppressed than uninfected individuals. This suggests perturbation of the CD4+ memory T cell compartment, in which a viral reservoir persists in HIV-1-infected individuals with effective ART. Modulation of restriction factor expression, or overrepresentation of cell subsets that intrinsically express these restriction factors at lower levels could result in the distinct expression of restriction factors observed in treated infected individuals.

The BET family in immunity and disease

“…However, in some rare cases (e.g., in memory CD4+ T cells in HIV-1-infected individuals), BRD4 expression is downregulated, which may be a consequence of increased immune activation because of the opposing effect on expression induced by interferon (IFN) in viremic HIV-1 infection. 38 It is also worthy to note that BRD4 function is not completedly determined by the change of its expression, as it also occupies essential roles in various pathophysiological processes with no detectable change in its expression, such as in pseudorabies virus infection, chronic obstructive pulmonary disease, and spinal cord injury. [39][40][41] The expression of BRD4 changes inversely in different types of cells even in the same disease state.…”

Pharmacological Modulation of BET Family in Sepsis

“…Normally, the expression of BRDT is restricted to the testis, while the expression of BRD2, BRD3, or BRD4 is commonly found in the nucleus of other cells (including immune cells). Under pathological conditions, the expression of BETs may be further changed (upregulation or downregulation) to meet the requirements for orchestrating a genetic regulatory response ( Bachtel et al, 2019 ; Hong et al, 2020 ). In the case of sepsis, according to the type of pathogen infection, the expression of BRD2, BRD3 or BRD4 shows heterozygosity and diversity in immune cells.…”

“…In the case of sepsis, according to the type of pathogen infection, the expression of BRD2, BRD3 or BRD4 shows heterozygosity and diversity in immune cells. For example, BRD4 expression can be up-regulated, down-regulated or unchanged in activated macrophages or memory CD4 + T cells during virus infection ( Bachtel et al, 2019 ). The expression profile of the BETs may not be a good biomarker of sepsis, although they have functions in innate immunity (discussed later).…”