Elsevier

Clinical Immunology

Volume 141, Issue 3, December 2011, Pages 253-267
Clinical Immunology

Review
The role of naïve T-cells in HIV-1 pathogenesis: An emerging key player

https://doi.org/10.1016/j.clim.2011.09.002Get rights and content

Abstract

Functional naïve T-cells are critical for an effective immune response to multiple pathogens. HIV leads to a significant reduction in CD4+ naïve T-cell number and impaired function and there is incomplete recovery following combination antiretroviral therapy (cART). Here we review the basic homeostatic mechanisms that maintain naïve CD4+ T-cells and discuss recent developments in understanding the impact of HIV infection on naïve CD4+ T-cells. Finally we review therapeutic interventions in HIV-infected individuals aimed at specifically enhancing recovery of naïve CD4+ T-cells.

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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