The role of naïve T-cells in HIV-1 pathogenesis - Burnet Institute

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Clinical Immunology (2011) 141, 253–267

REVIEW

The role of naïve T-cells in HIV-1 pathogenesis:An emerging key playerGabriela Khoury a, d, Reena Rajasuriar a, e,Paul U. Cameron a, b, c, d, Sharon R. Lewin a, c, d,⁎

a Department of Medicine, Monash University, 85 Commercial Road, Melbourne Victoria, 3004, Australiab Department of Immunology, Monash University, 85 Commercial Road, Melbourne Victoria, 3004, Australiac Infectious Diseases Unit, Alfred Hospital, 85 Commercial Road, Melbourne, Victoria, 3004, Australiad Centre for Virology, Burnet Institute, 85 Commercial Road Melbourne, Victoria 3004, Australiae Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Received 8 July 2011; accepted with revision 8 September 2011Available online 17 September 2011

⁎ Corresponding author at: Infectious9076 2431.

E-mail address: [email protected]

1521-6616/$ - see front matter © 2011doi:10.1016/j.clim.2011.09.002

KEYWORDSNaïve T-cells;HIV-1;IL-7;Immune reconstitution;Antiretroviral therapy;Reservoirs

Abstract Functional naïve T-cells are critical for an effective immune response to multiplepathogens. HIV leads to a significant reduction in CD4+ naïve T-cell number and impaired func-tion and there is incomplete recovery following combination antiretroviral therapy (cART). Herewe review the basic homeostatic mechanisms that maintain naïve CD4+ T-cells and discuss re-cent developments in understanding the impact of HIV infection on naïve CD4+ T-cells. Finallywe review therapeutic interventions in HIV-infected individuals aimed at specifically enhancingrecovery of naïve CD4+ T-cells.© 2011 Elsevier Inc. All rights reserved.

Diseases Unit, Alfred Hospital

.au (S.R. Lewin).

Elsevier Inc. All rights reserve

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2542. Naïve T-cell homeostasis: insights from murine models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

2.1. Homeostatic expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2542.2. Homeostatic proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

3. Naïve T-cell homeostasis, HIV infection and the impact of cART . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2563.1. Naïve T-cell number . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2563.2. Naïve T-cell function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

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254 G. Khoury et al.

3.2.1. Response to IL-7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2573.2.2. TCR diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2573.2.3. Response to neo-antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

4. HIV infection of naïve T-cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2574.1. Infection of naïve T-cells in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

4.1.1. Role of chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2584.1.2. Role of IL-7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2584.1.3. Tissue microenvironment and abortive infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2584.1.4. DC-naïve T-cell interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

4.2. Infection of thymocyte subsets in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2584.3. Infection of naïve T-cells in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

4.3.1. Total and integrated HIV DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2584.3.2. Viral compartmentalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2594.3.3. Viral co-receptor usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

5. Therapeutic approaches to enhance naïve T-cell recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2605.1. Exogenous IL-2 therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2605.2. Exogenous IL-7 therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

5.2.1. Animal preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2605.2.2. Human clinical trials: HIV-infected patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2605.2.3. IL-7 Receptor polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

5.3. Other novel therapeutic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2616. Outstanding research questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2617. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

1. Introduction

HIV infection is characterized by substantial depletion of CD4+T-cells including recent thymic emigrants, naïve T-cells andmemory T-cells. Following control of HIV replication witheffective 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 withnon-AIDS events including cardiovascular disease, liver diseaseand malignancy [1–4]. Therefore despite the substantialreduction in morbidity and mortality from cART, life expec-tancy has still not returned to normal [5,6]. A detailed under-standing of naïve CD4 T-cell homeostasis is required in order todevelop novel strategies to enhance the quality of immune re-constitution following cART.

2. Naïve T-cell homeostasis: insights frommurinemodels

Naïve T-cells are characterized by the expression of surfacemarkers CD45RA, CD27, CD28, CD62L, CCR7 and the IL-7receptor [7,8]. Naïve T-cells exit the thymus following matu-ration and are enriched for T-cell receptor excision circles(TREC) and express the surface marker platelet endothelialcell adhesion molecule-1 (PECAM-1), also known as CD31 [9].Naïve T-cells circulate between the blood and the lymphoidtissue driven by cell surface markers CD62L and CCR7 [10].The number of naïve T-cells in blood remains relativelyconstant throughout adult life despite continuous stimulationwith foreign antigens and a dramatic reduction in thymic out-put with age. Maintenance of naïve T-cells in adults is largelydependent on homeostatic proliferation which leads to a

decrease in CD31 expression and TREC concentration result-ing in an increase in the proportion of CD31- naïve T-cellswith aging [9,11]. The mechanisms which drive homeostaticproliferation of naïve T-cells in humans are not fully under-stood, however extensive studies in murine models havedemonstrated multiple factors are involved in both post-thymic survival and proliferation of naïve T-cells. Exposureto the cytokine IL-7 and contact with major histocompati-bility complex (MHC) molecules presenting self-peptidesthrough the T-cell receptor (TCR) within secondary lym-phoid tissue are both critical for naïve T-cell homeostasis[12–15]. (See Fig. 1).

2.1. Homeostatic expansion

In lymphopenic murine models, adoptive transfer of naïve T-cells results in a biphasic increase in naïve T-cells with bothrapid and slow proliferation phases. Rapid proliferation (or ho-meostatic expansion) was associated with conversion of naïveT-cells into an effector/memory phenotype [16,17]. There arediverse views on whether IL-7 is required for homeostatic ex-pansion which is thought to be dependent on the strength ofbinding between antigen and the TCR. Proliferative responsesfollowing low-affinity binding, as seen with self-peptides, isthought to be more dependent on IL-7 [12,18] compared tohigh-affinity cognate antigen binding (reviewed in [19]).

Naïve T-cell homeostatic expansion has also been shown tobe associated with exposure to microbial products. Followingadoptive transfer of T-cells from immunocompetent BALB/cThy1.1 mice to mice with severe combined immunodeficien-cy (SCID) that have been raised in a germ-free environment,there was little naïve T-cell proliferation, activation or

Figure 1 Naïve T-cell homeostasis. (A) Precursor T-cells from the bonemarrow undergomaturation in the thymus through positive andnegative selection. (B) Recent thymic emigrants (blue) leave the thymus and enter the periphery expressing CD45RA+CCR7+CD62L+CD31+(blue square) and containing high concentrations of T-cell Receptor Excision Circles (TREC, blue circle). Naïve T-cells can then undergodifferent outcomes, including (C) homeostatic proliferation following contact with IL-7 and self peptide presented by antigen presentingcells resulting in the production of naïve T-cells with reduced concentration of TREC and decreased expression of CD31 (purple) or (D)conversion to memory/effector cells (orange and pink) which are CD45RO+CD45RA− CD31−, following presentation of foreign antigenby antigen presenting cells (green).

The role of naïve T-cells in HIV-1 pathogenesis: An emerging key player 255

differentiation into a memory/effector phenotype suggestingthat exposure to environmental pathogens my contribute tonaïve T-cell expansion [20]. In addition, in mice who havehad chemical ablation of the thymus, microbial products inplasmawere elevated and there was an increase in chronic im-mune activation thought to be secondary to a reduction in cir-culating naïve T-cells and loss of gut integrity [21]. Therefore,naïve T-cell homeostatic expansion is influenced by exposureto environmental antigens and loss of naïve T-cells may inturn indirectly influence gut integrity. Given HIV infection ischaracterized by high levels of circulating lipopolysaccharide(LPS) and significant abnormalities in the gastrointestinal(GI) tract mucosa, these data may account for a significantchange in naïve T-cell homeostasis in HIV infection [22–24].

2.2. Homeostatic proliferation

In addition to rapid proliferation, adoptive transfer of naïveT-cells also leads to slow proliferation (also called homeostatic

proliferation) where the naïve phenotype is maintained and isdependent on IL-7 [16,17,25,26]. When naïve T-cells wereadoptively transferred into IL-7-deficient mice, survival ofthese cells was significantly compromised [12]. Survival ofnaïve T-cells was also dependent upon ongoing contact withself-peptide through presentation by either MHC Class I or IIand interaction with TCR of CD8+ and CD4+ naïve T-cellsrespectively [14,15,27,28].

A recent study suggested that the source of IL-7 also playsan important role in homeostatic proliferation of CD4+ naïveT-cells [29]. Following adoptive transfer of T-cells intolymphopenic mice deficient in recombination–activationgene-1 (Rag1−/−), CD8+ T-cells underwent proliferation inresponse to elevated peripheral IL-7 levels while proliferationof CD4+ naïve T-cells required the presence of dendritic cells(DCs) for both IL-7 and contact with MHC class II. The authorsdemonstrated that during lymphopenia, when IL-7 levelswere elevated, a subset of DCs that express the IL-7 receptorα chain (CD127) down-regulate MHC class II by negative feed-back [29]. This reduced the ability of the DC to interact with


the CD4+ naïve T-cell and therefore prevented proliferation. Itis unknown whether similar mechanisms involving CD127-pos-itive DCs exist in humans.

3. Naïve T-cell homeostasis, HIV infection and theimpact of cART

3.1. Naïve T-cell number

Following HIV infection there is a significant decline in numberand function of naïve CD4+ T-cells in the blood and lymphnode compared to healthy individuals [30–34]. (summarized inTable 1) The reduction in naïve T-cells is likely multi-factorialand secondary to reduced thymic function, increased naïve T-cell proliferation, enhanced immune activation and direct HIVinfection [30–32,35]. Collagen deposition in the paracorticalT-cell zones of the lymphoid tissue also plays a critical role inlimiting naïve T-cell homeostasis [36,37]. Recent work in bothSIV-infected macaques and HIV-infected humans demonstratedthat following SIV/HIV infection, increased production of TGF-βin lymphoid tissue resulted in procollagen production and depo-sition of collagen fibrils [38]. This resulted in restricted T-cellaccess to the fibroblastic reticular cell (FRC) network which isthemajor source of the survival factor IL7, resulting in apoptosisand depletion of naïve CD4+ T-cells. The loss of naïve T-cells inturn, removed a major source of lymphotoxin-β, a survival fac-tor for FRCs [38]. The resulting loss of FRCs and the loss of IL-7produced by FRCs may thus perpetuate a vicious cycle of

Table 1 Naïve T-cell abnormalities in the setting of HIV infectio

Compartment assessed Abnormality in naïve T-cells in H

Blood↓ Numbers of naïve T-cells and R↑ CMV responses associated with↑ Expansion proliferation (Ki67)↓ Cell cycle entry and proliferati↓ Co-stimulatory response (CD27↑ Signaling (Basal STAT5 phospho↓ Survival (↓ Bcl-2)↑ Phosphorylated STAT5 in cytop↓ Phosphorylated STAT5 nuclear

Lymph node↓ Number of naïve T-cells (TREC↑ Number of naïve T-cells (CD45RCollagen deposition in•Paracortical T zones•High endothelial venules•Fibroblastic reticular cell netw

↑ Distance between IL-7 source a↓ Access to IL-7↑ Naïve T-cell apoptosis (TUNEL+

Gastro-intestinal tract↓ CD4+ T cells (naïve, effector a↑ Microbial translocation (↑ LPS,↑ Fibrosis

depletion of naïve CD4+ T-cells and the FRC network in the set-ting of untreated HIV infection.

HIV infection leads to significant depletion of total muco-sal CD4+ T-cells in the GI tract which allow for migration ofmicrobial products into the systemic circulation [22,24]. Mi-crobial products, specifically LPS, can drive DC activation vialigation of toll like receptors (TLR) leading to elevated pro-inflammatory cytokines and enhanced T-cell proliferation[22,39,40]. Microbial products may also be responsible forenhanced naïve T-cell proliferation as demonstrated inmouse models but not yet confirmed in human studies[20,21]. More recently, the contribution of cytomegalovirus(CMV) co-infection to naïve T-cell proliferation and deple-tion has been explored. HIV-infected patients with strongCMV-specific T-cell responses had fewer naïve T-cells [41].The authors suggested that the loss of naïve T cells couldbe due to movement of naïve T-cells into the large pool ofCMV-specific memory T-cells leading to an adverse effecton total CD4+ T-cell immune recovery following cART.

Following initiation of cART, naïve T-cell proliferation de-creases; thymic output increases and the total number ofnaïve T-cells significantly increases [30,32,33,35]. However,the numbers of naïve T-cells rarely reach normal levels inadults even after more than 7 years of cART [42]. In contrast,in HIV-infected children, naïve T-cells reached normal levelsfollowing cART, and recovery of thymic output was indepen-dent of age and time of initiation of cART [43]. A recentstudy showed that naïve T-cell count at initiation of cARTcould predict successful immune reconstitution [44]. In thiscase, immune reconstitution was defined as an increase of

n.

IV (measurement) Reference

TE (CD45RA+, CD45RA+ CD62L+, TREC) [30–32,34]reduced number of naïve T-cells [41]

[31]on (Ki67, CFSE) [48,49]+ CD28) [49]rylation) [50,52]

[50]lasm [52]localisation [52]

) [32]A+ CD62L+, TREC) [34]

[37][36]

ork [38]nd naïve T-cells (CD45RA+) [38]

[38]) [38]

nd memory) [23,137,138]16s rDNA) [22,139]

[140]


100–200 CD4+ T-cells after 2 years on therapy. There is a needto further understand why recovery of naïve T-cells is im-paired following cART. The role of age, nadir CD4 T-cellcount or other biological factors that may enhance lymphnode fibrosis or impair thymic output remains to be furtherexplored.

3.2. Naïve T-cell function

Abnormalities in naive.

3.2.1. Response to IL-7The dramatic depletion of CD4+ T-cells in HIV infection is alsoassociated with significant functional defects in naïve T-cells(summarised in Table 1). HIV infection is associated with in-creased systemic levels of IL-7, low surface expression of theα chain of the IL-7 receptor (lL7Rα), CD127, and impaired re-sponse to IL-7 [45–47]. Naïve T-cells from HIV-infected indi-viduals had a reduced capacity to expand followingstimulation with TCR ligation and IL-7 [48]. In addition,CD31+ naïve T-cells, a subset of naïve T-cells that have re-cently left the thymus and not undergone proliferation[9,11], failed to express the co-stimulatory molecules CD28and CD27 after TCR stimulation [49]. Following TCR engage-ment of CD31- naïve T-cells, there was an increase in co-stim-ulatory molecules but the cells were unable to enter cell cycle[49]. These data demonstrate discreet functional defects inresponse to IL-7 and TCR engagement in the setting of HIV in-fection, in addition to reduced total number of naïve T-cells.

IL-7 signaling which occurs through the STAT5 pathway hasalso been shown to be altered during HIV infection. The basallevel of STAT5 phosphorylation was elevated in both naïve andmemory CD4+ T-cell subsets in patients receiving cART, whowere viremic and aviremic [50]. Expression of CD127 onnaïve T-cells and the ability of IL-7 to bind to the IL-7R onnaïve T-cells in patients on cART were similar to healthycontrols [50]. Recent analysis of signaling pathways in CD4+T-cells from viremic and aviremic patients also suggestedthat naïve CD4+ T-cells, in contrast to memory CD4+ T-cells,were able to sustain CD127-STAT5 signaling [51]. However,despite normal IL7 binding and sustained IL7R signaling inHIV-infected patients, the expression of the survival proteinBcl-2 was reduced in naïve T-cells from both viremic andcART-treated patients, consistent with a post-receptor blockthat prevented the induction of downstream pro-survivalsignals [50]. A study of viremic patients attributed this out-come to an increased accumulation of phosphorylated STAT5within the cytoplasm due to the inability to enter the nucleus[52]. The multiple defects in signaling pathways important forsurvival of naïve and memory T-cells could therefore play animportant role in limiting the capacity for CD4+ T-cell recov-ery following cART.

Following long-term cART in HIV-infected adults [53], andchildren [54], the concentration of IL-7 reduces to normallevels. One multivariate analysis showed that an increase inthe mean CD4+ T-cell count in patients was associated withincreased IL-7 responsiveness and this was independent ofT-cell activation, PD-1 expression, CCR5 expression and IL-7plasma levels [55]. In addition, patients on suppressivecART with a complete immunological response (≥500 CD4+T-cells/mm3 ≥5 years after initiation of ART), demonstrated

higher functional response to IL-7 (measured by STAT5 phos-phorylation), which correlated with increased total andnaïve T-cell levels compared to patients with incompleteresponses (CD4 b500 cells/μl) [55]. Other studies have shownthat defects in IL-7 responsiveness were only partiallycorrected with cART while levels of IL-7 remained elevatedand IL-7 receptor signaling defects were still present in manypatients following cART [50,56–58].

3.2.2. TCR diversityTCR diversity is also altered in patient with HIV infection. TCRdiversity is quantified by the length of the hypervariable CDR3Vβ regions of the TCR [59–62]. In healthy individuals the mul-tiple CDR3 lengths follow a Gaussian distribution but in HIV in-fection this distribution is skewed and is associated withdisease progression and accelerated loss of total CD4+ T-cellsin both adults and children [59–62]. Translocation of microbialproducts as well as the HIV glycoprotein (gp)160 which can in-duce superantigen responses in specific Vβ groups can alsolead to a skewed TCR repertoire [63]. In individuals whohave a poor immunological response to cART (b20% increasein CD4+ T-cells from baseline or do not reach 200 cells/μl)there was an increased expansion in some Vβ groups and thiswas associated with reduced naïve T-cell number and thymicoutput [58]. Two longitudinal studies have shown that despitean increase in total CD4+ T-cell count on long-term cART,CD4+ T-cell subsets remain skewed [64,65].

3.2.3. Response to neo-antigensA reduction in functional responses to new antigens and vacci-nations has also been associated with late initiation of cARTand was most likely due to skewing of the proportion of CD4+T-cell populations and depletion of naïve T-cells [66]. Otherstudies have shown that despite increases in CD4+ T-cells tolevels >500 CD4+ T-cells with long-term cART, responses toneoantigens through vaccinations were lower in HIV-infectedindividuals compared to healthy controls [67]. Lack of cellularresponse to neoantigens has also been observed in childrenand adolescents vaccinated during their first year on cART[68]. One possible explanation for these findings is a defectin naïve T-cell proliferation in response to neoantigen [69].The implications of long-term impaired naïve T-cell recoveryare unclear but it is highly likely that impaired naïve T-cellnumber and functionwill contribute to ongoing immune dysre-gulation in patients on cART.

4. HIV infection of naïve T-cells

One potential mechanism for depletion and impaired functionof naïve T-cells is that HIV can directly infect naïve T-cellsboth in vivo and in vitro. However the extent of infection,the impact of HIV infection on function and the effect ofcART on the reservoir of infected naïve T-cells is less clear.

4.1. Infection of naïve T-cells in vitro

Naïve CD4+ T-cells are relatively resistant to HIV infection invitro but in some conditions, direct infection can occur[70–72]. Infection of naïve T-cells with both CXCR4-using (X4)and CCR5-using (R5) viruses can lead to integration but the effi-ciency of infection of naïve CD4+ T-cells was significantly lower


than in resting memory CD4+ T-cells [70]. In vitro infection ofnaïve T-cells was associated with accumulation of partial or in-complete viral transcripts and delayed viral integration but themajor block to direct infection of naïve T-cells appears to be de-creased efficiency of viral fusion [70,73]. Viral fusion in naïve T-cells can be significantly enhanced in viruses that co-express ve-sicular stomatitis virus (VSV) and R5 envelope protein, but fu-sion was inefficient with VSV or R5 env protein alone [71]. Themolecular mechanisms for this observation are currentlyunclear.

4.1.1. Role of chemokinesOur laboratory recently demonstrated that direct infection ofresting CD4+ T-cells can be established following incubationwith chemokines that bind to chemokine receptors highlyexpressed on the surface of resting T-cells, including CCL19and CCL21 which both bind to CCR7 which is highly expressedon both naïve and memory T-cells [74,75]. However, thesechemokine mediated changes only facilitated infection ofresting memory and not naïve T-cells, [75]. Taken togetherthese data demonstrate that there are clear differences inthe ability of HIV to infect resting naïve and memory T-cellsand that the major block to infection of naïve T-cells occursearly in the viral life cycle, most likely at the level of viralfusion.

4.1.2. Role of IL-7The role of IL-7 in enhancing infection of naïve T-cells has alsobeen explored [76–79]. Naïve T-cells become more suscepti-ble to infection following culture with IL-7 [79]. Followingtreatment with IL-7, cord blood naïve T-cells and adult mem-ory T-cells, but not adult naïve T-cells, enter G1b phase ofcell cycle and become susceptible to infection with bothVSV-pseudotyped HIV and wild type HIV [76–78]. Total restingCD4+ T-cells treated with IL-7 together with the phosphatidy-linositol 3-kinase (PI3K) inhibitor, wortmannin, led to nochange in HIV infection suggesting that pathways other thanPI3K may be involved [78].

4.1.3. Tissue microenvironment and abortive infectionThe microenvironment may also have an important role insusceptibility of naïve T-cells to HIV infection. HIV infectionof resting naïve CD4+ T-cells was significantly enhancedwhen infection was performed using tonsil lymphoid tissueex vivo [80,81]. In contrast, when naive CD4+ T-cells werepurified from tonsil and cultured alone in vitro, HIV infectiondid not occur [80]. Differences between susceptibility to HIVinfection of naïve T-cells from lymphoid tissue and those iso-lated from the blood may be due to differences in the ex-pression of active and inactive forms of the cellular proteinAPOBEC3G [82].

When human lymphoid aggregated cultures (HLACs) fromtonsil were infected with X4-using virus, incomplete reversetranscription products accumulated within resting CD4+T-cells [72]. These incomplete transcripts triggered pro-apoptotic and pro-inflammatory cellular responses resultingin the death of resting CD4+ T-cells and may potentiallyexplain the significant CD4+ T-cell loss in HIV infection [72].These experiments however didn't distinguish betweenmemo-ry and naïve T-cells, so it is currently unknown if this occurs inboth T-cell subsets [72]. Enhanced apoptosis of resting CD4+T-cells isolated from the blood and infected in vitro has also

been described [83]. This newly describedmechanism of accu-mulation of incomplete reverse transcripts and abortive infec-tion could be an important contributing factor to naïve CD4+T-cell depletion in HIV-infected patients.

4.1.4. DC-naïve T-cell interactionsDCs located within the lymphoid tissue may play a role in en-hancing infection of naïve T-cells. One group has demonstrat-ed that in vitro co-culture of naïve T-cells with DCs cansignificantly enhance infection of naïve CD4+ T-cells [84],while others have shown no effect of DCs [70]. A study usingmonocyte-derived DCs (MDDCs) explored the efficiency ofMDDCs to transmit HIV to different T-cell subsets includingnaïve, central and effector memory subsets [84], The studyshowed that MDDC-mediated transmission of virus was depen-dent on virus co-receptor usage and co-receptor expression onthe target T-cell. MDDCs were only able to transfer X4 strainsto CD4+ naïve T-cells [84]. In other experiments, when restingT-cells were infected in the presence of DCs and then sortedinto naïve and memory cells, infection of naïve T-cells wasnot enhanced by the presence of DCs [70]. Other groups havedemonstrated that physical contact of total resting CD4+ T-cells with uninfected autologous immature-MDDCs increasedinfection of resting CD4+ T-cells [85]. This was not simply a re-sult of a mixed lymphocytic reaction as, an increase in activa-tion markers was only observed when a higher ratio of DC:T-cell was used [85].

Combined, these studies demonstrate that HIV infection ofnaïve T-cells requires additional signals, mediated by eithercytokines such as IL-7 or cell-cell contact via DC-T-cell con-tact, and that these signals are more likely to be present with-in the endogenous microenvironment of lymphoid tissue.

4.2. Infection of thymocyte subsets in vitro

HIV infection of thymocyte subsets could be themain source ofHIV-infected naïve T-cells in the periphery. All thymocytepopulations predominately express high levels of CXCR4 andlow levels of CCR5 making these cells more susceptible to in-fection with X4-using viruses [86,87]. However, HIV is able toenter thymocytes and undergo reverse transcription after in-fection with either X4 or R5-using viruses [88]. Our lab hasdemonstrated that thymic plasmacytoid dendritic cells playan important role in the infection of thymocytes throughtransfer of R5-using virus to both immature andmature thymo-cytes [89]. Various cytokines have differential effects on thy-mocyte infection. IL-7 alone or in combination with IL-4increased expression of CXCR4 and enhanced infection withX4-using viruses [87,90]. Thymocytes cultured with IL-2 andIL-4 expanded, the expression of both co-receptors increasedand thymocytes were more permissive to X4 and R5-using vi-ruses [90]. In addition, mature thymocytes cultured withTNF-α and IL-7weremore likely to become infected as a resultof IL-7 enhancing cell survival of mature cells [91].

4.3. Infection of naïve T-cells in vivo

4.3.1. Total and integrated HIV DNAIn contrast to findings in vitro, naïve T-cells are clearly infectedwith HIV in vivo, although at low levels compared with other T-cell subsets such as CD4+ memory T-cells [92–100];


(summarized in Table 2). Accurate quantification of HIV in naïveT-cells in vivo can be complicated by the surface markers usedto define naïve T-cells. If insufficient surface markers are usedto define a naïve T-cells (b3 specific markers) [7] then it is pos-sible that memory T-cell contamination may be contributing tothe assessment of naïve T-cells [101–103]. In addition, manystudies only assess total HIV DNA rather than integrated DNAwhich again may provide an over estimation of the number ofinfected naïve T-cells [92–97,99,100]. However, to furtherstrengthen the case that naïve T-cells are indeed infected invivo, replication competent virus has been detected in naïveT-cells from patients receiving cART [93,94,98,99].

There is conflicting data on whether specific naïve T-cellsubsets are preferentially infected. In one study, there was asignificantly higher concentration of HIV DNA in CD31- naïveT-cells compared with the CD31+ naive T-cells [92]. Thesefindings suggested that infection of naïve T-cells did notoccur in the thymus; but that infection potentially occurredfollowing naïve T-cell homeostatic proliferation in the pe-riphery. However, the samples in this study were fixedprior to sorting and this could have had an effect on the ef-ficiency of HIV DNA detection [92]. In a more recent longitu-dinal study of patients initiating cART, our group showedthat both CD31+ and CD31- naïve T-cell subsets wereinfected at similar frequency [95]. In addition we showedthat the contribution of naïve T-cells to the total reservoirincreased following cART [95]. Overall, even though the ab-solute number of infected naïve T-cells in patients on cART issignificantly smaller than infected memory T-cells, naïve T-cells expand significantly following cART and therefore mayrepresent a significant persistent reservoir in patients oncART.

Table 2 Detection of HIV infection of naïve T-cells in vivo. Studiepatients who are either on or off cART (upper rows without shading)

[92]

Reference

[93]

[94][95]

[96]

[97][98]

[99][100]

Patient Number (naïve/cART)

22 (11/11)

13 (13/0)

11 (4/7)10 (10/10)

26 (11/15)

102 (0/102)34 (0/34)

11 (0/11)3 (0/3)

CD4+ cells/µl(Median)

526

610

547143b

561

271581

582305

Plasma HIV RNA copies/ml (Median)

15,989

17,090

1,08565,150b

36,541(viremic)<40 (aviremic)

6,908<50

<20<20

Phenotype naïve T-cell

CD11a10

CD45RO—CDCD27+ CD31CD27+CD45RCD11a+CD57CD45RA+CDCD45RO—CDCD31+/—CD45RA+CCCD31+/—

CD45RA+CDCD45RA+ CCCD27+CD45RA+CDCD45RA+CD

–Not assessed.a Phylogenetic analysis.b Baseline sample at the beginning of longitudinal study.

Amore recent cross-sectional study looking at both viremicand aviremic patients showed that both CD31+ and CD31-naïve T-cell subsets were infected with HIV at similar frequen-cies and in some patients, infected naïve T-cells made a sub-stantial contribution to the overall pool of infected T-cells[96]. This study also showed that in CD31+ naïve T-cells fromboth viremic and aviremic patients, the concentration of HIVDNA positively correlated with IL-7 plasma levels, suggestinga possible function of IL-7 in the infection of naïve T-cells.

4.3.2. Viral compartmentalizationIn order to better understand the origin of infection of naïveT-cells, several groups have examined the phylogenetic rela-tionship between virus isolated from naïve T-cell subsets,memory cells and plasma. We recently showed that therewas no compartmentalisation of virus envelope sequences inCD31+ and CD31- naïve and memory T-cells subsets from pa-tients prior to and following cART [95]. Similar findings havebeen described in another study using sorted samples from pa-tients naïve to cART [93]. In a smaller cohort of aviremic pa-tients on cART for seven years, compartmentalization ofvirus in naïve T-cells was observed in two of the three patientsstudied [100]. In order to better understand the origin of infec-tion of naïve T-cells, these studies should be performed inlarger prospective studies of patients on long term cART.

4.3.3. Viral co-receptor usageBoth R5-using and X4 using virus has been isolated from naïve T-cells from HIV-infected patients [93–95,100]. In all of thesestudies naïve T-cells were predominantly infected with R5-using virus. However, two of the studies did detect some X4-using viruses within the naïve T-cell compartment [94,100]. It

s that have assessed HIV infection of naïve T-cells in HIV-infectedor on cART (lower rows, gray shading) are shown.

s

57—+/—O——

62L+28+

R7+

62L+R7+

62L+62L+

Total HIV DNA

Yes (CD31 neg >CD31pos)

Yes (total)

Yes (total)Yes (CD31+ = CD31 neg)Yes (CD31+ = CD31 neg)

Yes (total)—

Yes (total)Yes (total)

Integrated HIV DNA

—

—

Yes—

Yes CD31+ (10 cART—patients) —Yes

——

Replication competentvirus

—

Yes

Yes—

—

—Yes

Yes—

Compartment-alisationa

—

No

—No

—

——

—Yes (2/3)


still remains unclear how naïve T-cells become infected withR5-using viruses given the low expression of CCR5 on the surfaceof naïve T-cells. We have recently demonstrated in vitro thatthymic plasmacytoid DC are able to efficiently transfer R5-using virus to both immature and mature thymocytes providinga potential mechanism to explain R5-using infection of naïveT-cells [89].

5. Therapeutic approaches to enhance naïveT-cell recovery

In addition to cART, there is now increasing interest to de-velop immunotherapeutic agents that specifically enhanceCD4+ T-cell recovery, including naïve T-cells.

5.1. Exogenous IL-2 therapy

Administration of IL-2 to lymphopenic mice increased totalCD4+ T-cells including naïve, resting memory and activatedCD4+ T-cells [104]. Similar responses were seen in HIV-infected patients on cART who received IL-2 [105–107].Both thymic output and peripheral homeostatic proliferationcontributed to the increase in naïve CD4+ T-cells [104–109].In patients treated with cART and IL-2 there was a reductionin apoptosis of total and naïve CD4+ T-cells [106,110].

Two large, randomized international clinical trials of IL-2in patients on cART, Evaluation of Subcutaneous Proleukin ina Randomized International Trial (ESPRIT) [111] and Subcu-taneous, Recombinant Human Interleukin-2 in HIV-InfectedPatients With Low CD4+ Counts Receiving Active Antiretrovi-ral Therapy (SILCAAT) [112] showed no additional clinicalbenefit following administration of IL-2 to patients receivingcART. These studies demonstrated that IL-2 led to a clear in-crease in total CD4+ T-cell counts, including naïve CD4+ T-cells, but this did not lead to a reduction in opportunisticinfections or mortality, showing that IL-2 therapy had noadditional clinical benefit for patients on cART [111–113].Similar findings were observed in the Study of ALdesleukinWith and without AntiRetroviral Therapy, (STALWART),which tested intermittent IL-2 combined with peri-cyclecART in HIV-infected individuals who were cART-naïve andasymptomatic [114]. These studies demonstrated that anincrease in CD4+ T-cell number secondary to IL-2 did nottranslate to effective function and improved clinical out-comes and further work is needed to understand the biolog-ical basis for these findings.

5.2. Exogenous IL-7 therapy

5.2.1. Animal preclinical studiesAdministration of IL-7 to SIV-infected and uninfected cynomo-logus monkeys, baboons and macaques, induced proliferationof naïve CD4+ T-cells and a decline in the frequency of TRECconsistent with enhanced homeostatic proliferation [115–119]. Administration of IL-7 induced migration of T-cells tothe lymph node where they entered cell cycle [120] and great-er TCR diversity was observed consistent with enhanced thy-mic output [119]. Importantly, administration of IL-7 to SIV-infected macaques resulted in no increase in SIV viral load[116,117].

5.2.2. Human clinical trials: HIV-infected patientsThere have been two completed trials of recombinant human(rh) IL-7 in cART-treatedHIV-infected patients. In one study, pa-tients with CD4+ T-cell counts 100–400 cells/μl and HIV RNAb50 copies/ml had eight subcutaneous injections three timesper week over a 16 day period and two doses of rhIL-7 were ex-amined [121]. There was a preferential increase in both naïveand central memory T-cells following rhIL-7. Increases inCD4+ naïve T-cells peaked at day 14 and started to decline14 days after completion of rhIL-7. At the higher dose,four patients also experienced a transient increase in plas-ma HIV RNA [121].

The second trial was performed in HIV-infected patients withCD4+ T-cell counts >100 cells/μl, in patients with a viral load ofb50 or 50–50,000 copies/ml HIV RNA [122]. A transient increasein HIV RNAwas demonstrated in 6 out of 11 patients who hadHIVRNA b50 copies/ml at baseline. On day 1 following rhIL-7, therewas a significant decrease in circulating CD4+ and CD8+ T-cells.By day 14, the levels had increased but mainly consisted of cen-tral memory T-cells, with minimal increase in naïve T-cells. Thenumber of proliferating naïve T-cells increased compared tobaseline, however these were mainly CD8+ T-cells [122].

Aside from the effects of IL-7 on CD4+ T-cell number, IL-7can also have an impact on latently infected cells and possi-bly co-receptor usage of virus in vivo. In both clinical trials ofIL-7, some patients experienced a transient increase in plas-ma HIV RNA at the time of peak T-cell proliferation, whicheventually returned to b50 copies/ml [121,122]. There wasno significant increase in the concentration of cell-associatedHIV DNA in either PBMC or CD4+ T-cells following IL-7 [121].However, this study did not correct for the overall increasein total T-cell number following rhIL-7, meaning that the abso-lute number of infected cells (expressed as HIV copies/mlblood) may have increased as a result of proliferation of la-tently infected naïve, central memory or transitional memoryT-cells, as has recently been demonstrated ex vivo [98].Therefore, it is possible that IL-7 may induce proliferation ofboth uninfected and latently infected naïve and memory T-cells and it remains unclear if IL-7 will expand or activate la-tently infected cells. Clinical trials are currently underway totest this (ERAMUNE; www.clinicaltrials.gov).

IL-7 may also potentially lead to a change in HIV co-recep-tor usage. Following long-term culture of HIV-infected PBMCwith IL-7 in vitro, there was an increase in the expression ofCXCR4 on CD4+ T-cells, which led to a change in co-receptorusage from R5-using to X4-using virus [123]. The same groupalso suggested that increases in CXCR4 expression on CD4+ T-cells from HIV-infected patients could lead to the emergenceof R4-using viruses [124]. Using IL-7 as an immunotherapycould potentially have the same effect in vivo although todate this has not been demonstrated.

5.2.3. IL-7 Receptor polymorphismsIt is possible that response to endogenous and exogenous rhIL-7 is dependent upon differences in the IL-7R which are deter-mined by genetic polymorphisms. The IL-7R is composed of anα and common γ chain [125]. Four haplotypes of the gene cod-ing for IL-7Rα (CD127) have been described in Caucasians[126]. These haplotypes are defined by single nucleotide poly-morphisms located throughout the IL-7Rα gene and lead to al-ternative splicing ofmRNA resulting in varying ratios of solubleand membrane bound CD127 [127–129]. Using a multivariate

http://www.clinicaltrials.gov

Table 3 Outstanding research questions on naïve CD4+ T-cells and HIV pathogenesis.

Outstanding research questions

1. Are naïve T-cells infected in all patients or only a selectproportion?

2. At what stage of disease do naïve T-cells become infected?3. Are naïve T-cells preferentially infectedwith X4-using or R5-using

viruses?4. Does viral compartmentalization occur in naïve T-cell subsets?5. How do R5-using viruses infect naïve T-cells?6. How does self-peptide and microbial products drive naïve T-

cell proliferation in humans?7. Which surrogate markers of immune function should be used

in future clinical trials of immune based therapies?8. What genetic factors contribute to CD4 T-cell immune re-

constitution following cART?


analysis, we have recently shown that the IL-7Rα haplotype 2was significantly associated with more rapid recovery of CD4+T-cells >500 cells/μl following cART [53]. In addition, solubleCD127 (sCD127) levels in cART-treated HIV-infected patientswere significantly lower in individuals who were homozygousfor haplotype 2 than non-haplotype 2 carriers. A potential ex-planation for these findings is that high levels of sCD127“mops” up circulating IL-7 allowing for less efficient IL-7-related cell signaling and impaired CD4+ T-cell recovery. Eval-uation of these and other polymorphisms should be performedin other patient cohorts. In addition these polymorphisms maypotentially be important in determining how effectively a pa-tient responds to exogenous IL-7, although these studies havenot been performed to date.

5.3. Other novel therapeutic approaches

Other immunotherapies like Growth Hormone (GH), Keratino-cyte Growth Factor (KGF), and androgen blockade which areknown to improve thymopoiesis and thymic architecture regen-eration are also being considered for evaluation in HIV-infectedpatients. Other approaches could also include anti-fibroticagents that could potentially reduce lymph node fibrosis [38].

A randomized control trial of GH in a cohort of 46 HIV-infected patients receiving cART showed promising resultswith significant increases in thymopoiesis as measured byTREC concentration [130]. Studies in macaques have shownthat KGF targets epithelial cells, improves both naïve T-cellnumbers and TCR diversity [131] and also activates the pro-duction of IL-7 within the thymus [132]. At puberty when sexsteroid levels increase, the thymus decreases in size and thy-mic output significantly reduces. Therefore androgen block-ade may improve thymic output of HIV patients as shownfollowing castration in mouse models [133]. In addition, hypo-gonadal men have been shown to have an increased number ofRTE and following treatment with androgens, the levels of RTEdecline [134]. Sex steroid blockade using luteinizing-hormonereleasing hormone antagonists is currently used in the treat-ment of prostate cancer [133] and has also been trialed in pa-tients undergoing stem cell transplantations [135]. In both ofthese scenarios, thymic function and production of naïveT-cells were enhanced. No trials have yet been performed inthe setting of HIV infection.

6. Outstanding research questions

Many outstanding research questions remain about naive T-cells and HIV infection (Table 3). Most of our detailed under-standing of the mechanisms of naïve T-cell homeostasis is de-rived from mouse models. The effects of self-peptide andmicrobial translocation in driving enhanced naïve T-cell prolif-eration should be further explored in ex vivo human models.New interventions targeting immune reconstitution like exog-enous IL-7 have shown promise in clinical trials. However, amajor challenge for the field is to determine how best to eval-uate efficacy of immunomodulators such as IL-7 given the ob-servation of enhanced CD4+ T-cell recovery but noimprovement in clinical endpoints in the recent IL-2 studies.The efficacy of adjunct immunomodulatory therapy withcART can no longer be evaluated on the basis of CD4+ T-cellnumber alone and large randomised trials with clinical

endpoints with better surrogate markers of immune functionother than the number of CD4+ T-cells alone will be needed.The varying responses in immune reconstitution between indi-viduals may potentially be predicted by genetic differencesand larger genomewide association studies similar to those re-cently conducted on HIV controllers [136] need be conductedto assess the determinants of CD4+ T-cell reconstitution.These studies will be important in identifying novel therapeu-tic targets to enhance immune recovery.

7. Conclusion

Successful immune reconstitution requires an increase intotal CD4+ T-cells as well as the recovery of CD4+ naïve T-cell number and function. Understanding the multiple fac-tors involved in naïve T-cell homeostasis and proliferationwill allow for the development of new strategies to enhanceimmune reconstitution.

Role of the funding source

G.K is a recipient of the National Health and Medical ResearchCouncil (NHMRC) biomedical postgraduate scholarship.

S.R.L is funded by the NHMRC and Alfred Foundation and isan NHMRC Practitioner Fellow

P.U.C and S.R.L were funded by an NHMRC program grant forthis work.

R.R is a recipient of the King Scholarship from the Malaysiangovernment.

Conflict of interest statement

The author(s) declare that there are no conflicts of interest.

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The role of naïve T-cells in HIV-1 pathogenesis - Burnet Institute

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