Development of Skewed Functionality of HIV-1-Specific Cytotoxic CD8+ T Cells from Primary to Early Chronic Phase of HIV Infection

Abstract

In recent years, the prevalence of HIV-1 infection has been rapidly increasing among men who have sex with men (MSM). However, it remains unknown how the host immune system responds to the infection in this population. We assessed the quantity of HIV-specific CD8+ T-cell responses by using Elispot assay and their functionalities by measuring 5 CD8+ T-cell evaluations (IL-2, MIP-1β, CD107a, TNF-α, IFN-γ) with flow cytometry assays among 18 primarily and 37 early chronically HIV-infected MSM. Our results demonstrated that subjects at early chronic phase developed HIV-specific CD8+ T-cell responses with higher magnitudes and more diversified functionalities in comparison with those at primary infection. However, populations with IL-2+ CD107a+ or in combination with other functionality failed to develop in parallel. The multifunctional but not monofunctional HIV-specific CD8+ T cells were associated with higher CD4+ T -cell counts and lower viral loads. These data revealed that prolonged infection from primary to early chronic infection could selectively increase the functionalities of HIV-specific CD8+ T cells in HIV-infected MSM population, the failure to develop IL-2 and cytotoxic functionalities in parallel may explain why the increased HIV-specific CD8+ T cells were unable to enhance the containment of HIV-1 replication at the early chronic stage.

CD8+ T‐cell effector function and transcriptional regulation during HIV pathogenesis

“…It stands to reason that if polyfunctionality or rapid perforin upregulation are responsible for control, they should be present during this critical time period. Similar to other reports (137, 146, 147), when we examined expression of IL-2, IFN-γ, TNF-α, MIP-1α, and CD107a, we found that HIV-specific CD8 + T cells are rarely polyfunctional during acute infection with the highest frequencies of responding cells represented by the expression of MIP-1α and CD107a singly or in combination (Makedonas G, Betts M, et al ., manuscript in preparation). In contrast to previous reports indicating perforin expression during acute infection is low (148, 149), we found that rapid perforin upregulation dominates the earliest HIV-specific CD8 + T-cell responses we could detect in nearly every acute subject (Makedonas G, Demers K, Betts M, et al ., manuscript in preparation).…”

Preserving HIV-specific T cell responses

“…This loss of CD8 + T cell function correlates with progressive infection [28]. New CD8 + T cell responses are generated following viral escape but are no longer associated with significant decreases in plasma viremia [29] despite the increase in the breadth of HIV-specific reactivity following early primary infection [23,30]. For CD4 + T cells, Env-specific and Gag-specific responses are detected within the first 30 days of infection [31].…”

MAVS Genetic Variation Is Associated with Decreased HIV-1 Replication In Vitro and Reduced CD4+ T Cell Infection in HIV-1-Infected Individuals

“…Although the breadth and magnitude of these responses are limited, the antiviral activity of these responses is associated with initial viral control and rapid selection of escape variants [ 38 , 39 , 40 ]. During the asymptomatic phase of infection, new T cell responses that target HIV escape variants increase in breadth, but eventually, the control of viremia is lost due to T cell dysfunction and viral escape [ 33 , 41 , 42 , 43 ].…”