Higher expression of human telomerase reverse transcriptase in productively-infected CD4 cells possibly indicates a mechanism for persistence of the virus in HIV infection.

Abstract

Mechanisms involved in survival of productively-infected memory CD4+cells after initial antigenic stimulation and their subsequent reversion to the resting state are critical for the development of a predominant replication-competent HIV reservoir. These mechanisms may also counter their elimination after HIV reactivation through latency-reversing agents (LRA). Thus, their evaluation is critical when using an appropriate HIV latency model that recapitulates the predominant replication-competent HIV reservoir to develop strategies for HIV eradication. The model for evaluating the possible survival mechanisms after T cell receptor (TCR) stimulation was developed by infecting memory CD4+cells with an HIV-1C primary isolate and cytokine secretion and gene expression patterns determined. Infected cells showed compromised functionality as evident from 6.8-fold lower secretion of IL-2 than from uninfected control cells. After TCR stimulation, the infected cells showed significantly higher fold increases in CD27 and CCR5 and smaller increases in CD5 mRNA over baseline values. Because CD27 expression may influence telomerase activity through AKT phosphorylation, CD27, human telomerase reverse transcriptase (hTERT) and pAKT expression in productively-infected cells from HIV-infected patients was evaluated by flow cytometry. HIV harbored in memory CD4+ cells was reactivated by HIV-1 envelope peptides, which have been shown to act as effective LRA. P24+CD4+cell showed significantly higher expression of CD27, hTERT and pAKT than P24-CD4+cells. These findings indicate compromised functionality of HIV-infected cells after TCR stimulation, which may interfere with their elimination by the immune system. They also indicate that pAKT and hTERT induction are possible survival mechanisms of productively-infected CD4+cells.