ReviewThe role of naïve T-cells in HIV-1 pathogenesis: An emerging key player
Highlights
► We review basic homeostatic mechanisms that maintain naïve CD4+ T-cells. ► Discuss recent developments in understanding how HIV infects naïve CD4+ T-cells. ► The impact of HIV infection on naïve CD4+ T-cell homeostasis. ► Perturbed homeostasis results in implications for successful immune reconstitution. ► Summarize novel therapeutic interventions that enhance naïve CD4+ T-cells recovery.
Introduction
HIV infection is characterized by substantial depletion of CD4+ T-cells including recent thymic emigrants, naïve T-cells and memory T-cells. Following control of HIV replication with effective combination antiretroviral therapy (cART), CD4+ T-cells recover to normal levels, in most but not all patients, and impaired CD4+ T-cell recovery has been associated with non-AIDS events including cardiovascular disease, liver disease and malignancy [1], [2], [3], [4]. Therefore despite the substantial reduction in morbidity and mortality from cART, life expectancy has still not returned to normal [5], [6]. A detailed understanding of naïve CD4 T-cell homeostasis is required in order to develop novel strategies to enhance the quality of immune reconstitution following cART.
Section snippets
Naïve T-cell homeostasis: insights from murine models
Naïve T-cells are characterized by the expression of surface markers CD45RA, CD27, CD28, CD62L, CCR7 and the IL-7 receptor [7], [8]. Naïve T-cells exit the thymus following maturation and are enriched for T-cell receptor excision circles (TREC) and express the surface marker platelet endothelial cell adhesion molecule-1 (PECAM-1), also known as CD31 [9]. Naïve T-cells circulate between the blood and the lymphoid tissue driven by cell surface markers CD62L and CCR7 [10]. The number of naïve
Naïve T-cell number
Following HIV infection there is a significant decline in number and function of naïve CD4+ T-cells in the blood and lymph node compared to healthy individuals [30], [31], [32], [33], [34]. (summarized in Table 1) The reduction in naïve T-cells is likely multi-factorial and secondary to reduced thymic function, increased naïve T-cell proliferation, enhanced immune activation and direct HIV infection [30], [31], [32], [35]. Collagen deposition in the paracortical T-cell zones of the lymphoid
HIV infection of naïve T-cells
One potential mechanism for depletion and impaired function of naïve T-cells is that HIV can directly infect naïve T-cells both in vivo and in vitro. However the extent of infection, the impact of HIV infection on function and the effect of cART on the reservoir of infected naïve T-cells is less clear.
Therapeutic approaches to enhance naïve T-cell recovery
In addition to cART, there is now increasing interest to develop immunotherapeutic agents that specifically enhance CD4+ T-cell recovery, including naïve T-cells.
Outstanding research questions
Many outstanding research questions remain about naive T-cells and HIV infection (Table 3). Most of our detailed understanding of the mechanisms of naïve T-cell homeostasis is derived from mouse models. The effects of self-peptide and microbial translocation in driving enhanced naïve T-cell proliferation should be further explored in ex vivo human models. New interventions targeting immune reconstitution like exogenous IL-7 have shown promise in clinical trials. However, a major challenge for
Conclusion
Successful immune reconstitution requires an increase in total CD4+ T-cells as well as the recovery of CD4+ naïve T-cell number and function. Understanding the multiple factors involved in naïve T-cell homeostasis and proliferation will allow for the development of new strategies to enhance immune reconstitution.
Role of the funding source
G.K is a recipient of the National Health and Medical Research Council (NHMRC) biomedical postgraduate scholarship.
S.R.L is funded by the NHMRC and Alfred Foundation and is an NHMRC Practitioner Fellow
P.U.C and S.R.L were funded by an NHMRC program grant for this work.
R.R is a recipient of the King Scholarship from the Malaysian government.
Conflict of interest statement
The author(s) declare that there are no conflicts of interest.
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2021, GenomicsCitation Excerpt :In this part of the results, we present statistically significant DEGs involved in previously described pathways of CD4+ T cells dysfunctions independently on whether they passed the filter of log2FC > 1.5. Relating to the review of genes and proteins involved in CD4+ TN cell dysfunctions presented by Khoury et al. [41] we compared, in our groups of controls, EA and LA patients, the expression of BCL2, CCR5, CCR7, CD27, CD28, GHR, IL7R, LTB, MKI67, PECAM, PTGS2, SELL, STAT5A, STAT5B (Fig. 7). The expression of BCL2 was significantly decreased in both EA and LA compared to controls.
Substantial induction of non-apoptotic CD4 T-cell death during the early phase of HIV-1 infection in a humanized mouse model
2021, Microbes and InfectionCitation Excerpt :The memory subpopulation of primary CD4 T cells is permissive for R5 and X4 HIV-1 infection, but infection is more efficient for R5 HIV-1 than X4 HIV-1 in vitro. In contrast, the naïve subpopulation is only permissive for X4 HIV-1 infection in vitro [33,34], but can be infected with R5 HIV-1 in vivo although at low levels compared with the memory subpopulation [35]. To confirm a pathogenicity of HIV-1 on CD4 T cells in hNOJ mice, we monitored the cell counts of whole, naïve, and memory CD4 T cells in PB up to 35 days post-challenge with HIV-1 harboring either DsRed or EGFP reporters with a distinct tropism (R5 HIV-1NL-AD8-D or X4 HIV-1NL-E, respectively).
Dasatinib protects humanized mice from acute HIV-1 infection
2020, Biochemical PharmacologyCitation Excerpt :Moreover, such viral control does not imply the clearance of the reservoir during cART. HIV-1 reservoir is located in higher proportion in central memory (TCM), stem cell-like memory (TSCM) and effector memory (TEM) CD4+ T cells [9–11], whereas terminally differentiated effector memory (TEMRA) and naïve (TN) CD4+ T cells show a minor contribution [10,12]. These latently infected cells remain undetectable for the immune system and cART until they are activated and begin T-cell expansion, proliferation and full viral replication [13].
Alteration of CCR6<sup>+</sup>CD95<sup>+</sup>CD4<sup>+</sup> naïve T cells in HIV-1 infected patients: Implication for clinical practice
2018, Cellular ImmunologyCitation Excerpt :Intriguingly, INRs failed to exhibit a correlation between CCR6+CD95+CD4+ TNA and CCR6+CD95+CD4+ TCM and displayed elevated ratio of CCR6+CD95+CD4+ TCM/TNA. The abnormalities were indicated by studies reporting that TNA were disturbed in INRs [36–38]. A previous report proposed disturbed thymic output of naïve Treg cells and excessive conversion from naïve Treg to hyperproliferatively differentiated Treg cells were associated with poor immune reconstitution [36].
Elevated CD57 and CD95 expressions are associated with lower numbers of CD4<sup>+</sup> recent thymic emigrants in HIV-1 infected immune responders following antiretroviral treatment
2014, Immunology LettersCitation Excerpt :Our study focused on CD4+ CD31+ naïve T cells for their critical role to maintain and to reconstitute overall CD4+ T cell counts [17]. Acquiring a broad TCR diversity for responding to neo-antigens, functional CD4+ CD31+ naïve T cells are also important for an effective immune response against chronic infection by highly mutating virus, such as HIV-1 or HCV [17–19]. Loss of number and function of CD4+ CD31+ naïve T cells after HIV-1 viremia leads to severe immunodeficiency and accelerates the disease progression [18–21].