Despite advances in slowing the progression of acquired immunodeficiency syndrome (AIDS), there is no viable cure for human immunodeficiency virus (HIV). The challenge toward a cure is mainly the formation and maintenance of a latent reservoir of cells that harbor the virus in both replication-competent and replication-defective states. This small niche of quiescent cells has been identified to reside primarily in quiescent and memory CD4+ T cells, but parameters that could reliably distinguish an infected T cell from an uninfected one, if any, are not clear. In addition, the migratory properties and specific anatomical reservoirs of latent T cells are difficult to measure at a high resolution in humans. A functional cure of HIV would require targeting this population using innovative new clinical strategies. One constraint toward the empirical development of such approaches is the absence of a native small animal model for AIDS. Since HIV does not efficiently infect murine cells, probing molecular-genetic questions involving latently infected T cells homing to deep tissue sites, interacting with stroma and persisting through different treatment regimens, is challenging. The goal of this article is to discuss how examining the dynamics of T cells in mouse models can provide a framework for effectively studying these questions, even without infecting mice with HIV. The inflammatory and cytokine milieu found in early human HIV infections are being increasingly understood as a result of clinical measurements. Mouse studies that recreate this milieu can potentially be used to subsequently map the fate of T cells activated in this context as well as their migratory routes. In essence, such a framework could allow complementary studies in mice to enhance our understanding of aspects of the biology of HIV latency. This can be the basis of a modular approach to small animal HIV modeling, amenable to preclinical curative strategy development.
Get full access to this article
View all access options for this article.
References
1.
Abdel-MohsenM, ChavezL, TandonR, et al.Human Galectin-9 is a potent mediator of HIV transcription and reactivation. PLoS Pathog, 2016; 12:e1005677.
2.
AbnerE, and JordanA. HIV “shock and kill” therapy: in need of revision. Antivir Res, 2019; 166:19–34.
3.
AbrahamsM-R, JosephSB, GarrettN, et al.The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation. Sci Transl Med, 2019; 11:eaaw5589.
4.
AdonaiN, AdonaiN, NguyenKN, et al.Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc Natl Acad Sci U S A, 2002; 99:3030–3035.
5.
AhlenstielCL, SymondsG, KentSJ, et al.Block and lock HIV cure strategies to control the latent reservoir. Front Cell Infect Microbiol, 2020; 10:424.
6.
AkkinaR. New generation humanized mice for virus research: comparative aspects and future prospects. Virology, 2013; 435:14–28.
7.
AkkinaR, AllamA, BalazsAB, et al.Improvements and limitations of humanized mouse models for HIV research: NIH/NIAID “Meet the Experts” 2015 workshop summary. AIDS Res Hum Retroviruses, 2016; 32:109–119.
8.
AllamA, MajjiS, PeachmanK, et al.TFH cells accumulate in mucosal tissues of humanized-DRAG mice and are highly permissive to HIV-1. Sci Rep, 2015; 5:10443.
9.
AnanworanichJ, DubeK, and ChomontN. How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?. Curr Opin HIV AIDS, 2015; 10:18–28.
10.
AndoM, ItoM, SriratT, et al.Memory T cell, exhaustion, and tumor immunity. Immunol Med, 2020; 43:1–9.
11.
AntonucciJM, KimSH, St. Gelais C, et al. SAMHD1 Impairs HIV-1 gene expression and negatively modulates reactivation of viral latency in CD4+ T cells. J Virol, 2018; 92:e00292–00218.
12.
BachmannN, von SiebenthalC, VongradV, et al.Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART. Nat Commun, 2019; 10:3193.
13.
BadiaR, BallanaE, CastellvíM, et al.CD32 expression is associated to T-cell activation and is not a marker of the HIV-1 reservoir. Nat Commun, 2018; 9:1–10.
14.
BainsI, AntiaR, CallardR, et al.Quantifying the development of the peripheral naive CD4+ T-cell pool in humans. Blood, 2009; 113:5480–5487.
15.
BarKJ, CoronadoE, Hensley-McBainT, et al.Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology. J Virol, 2019; 93:e00372–00319.
16.
BartonKM, and PalmerSE. How to define the latent reservoir: tools of the trade. Curr HIV/AIDS Rep, 2016; 13:77–84.
17.
BaxterAE, RussellRA, DuncanCJA, et al.Macrophage infection via selective capture of HIV-1-infected CD4+T cells. Cell Host Microbe, 2014; 16:711–721.
18.
BoritzEA, DarkoS, SwaszekL, et al.Multiple origins of virus persistence during natural control of HIV infection. Cell, 2016; 166:1004–1015.
19.
BreenEC, RezaiAR, NakajimaK, et al.Infection with HIV is associated with elevated IL-6 levels and production. J Immunol, 1990; 144:480.
20.
BrenchleyJM, SchackerTW, RuffLE, et al.CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med, 2004; 200:749–759.
21.
BrenchleyJM, PriceDA, SchackerTW, et al.Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med, 2006; 12:1365–1371.
22.
BrodinJ, ZaniniF, TheboL, et al.Establishment and stability of the latent HIV-1 DNA reservoir. Elife, 2016; 5:e18889.
23.
BrunerKM, WangZ, SimonettiFR, et al.A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature, 2019; 566:120–125.
24.
BukrinskyMI, StanwickTL, DempseyMP, et al.Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science, 1991; 254:423–427.
25.
BuzonMJ, SunH, LiC, et al.HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med, 2014; 20:139–142.
26.
ChavezL, CalvaneseV, and VerdinE. HIV latency is established directly and early in both resting and activated primary CD4 T Cells. PLoS Pathog, 2015; 11:e1004955.
27.
ChengL, MaJ, LiG, et al.Humanized mice engrafted with human HSC only or HSC and thymus support comparable HIV-1 replication, immunopathology, and responses to ART and immune therapy. Front Immunol, 2018; 9:817.
28.
ChouCS, RamiloO, and VitettaES. Highly purified CD25- resting T cells cannot be infected de novo with HIV-1. Proc Natl Acad Sci U S A, 1997; 94:1361–1365.
29.
ChunT-W, EngelD, BerreyMM, et al.Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A, 1998; 95:8869–8873.
30.
ChurchillMJ, DeeksSG, MargolisDM, et al.HIV reservoirs: what, where and how to target them. Nat Rev Microbiol, 2016; 14:55–60.
31.
CoelhoLE, TorresTS, VelosoVG, et al.Pre-exposure prophylaxis 2.0: new drugs and technologies in the pipeline. Lancet HIV, 2019; 6:e788–e799.
32.
CohnLB, da SilvaIT, ValierisR, et al.Clonal CD4(+) T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat Med, 2018; 24:604–609.
33.
ColombF, GironLB, PremeauxTA, et al.Galectin-9 mediates HIV transcription by inducing TCR-dependent ERK signaling. Front Immunol, 2019; 10:267.
34.
DescoursB, PetitjeanG, López-ZaragozaJL, et al.CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature, 2017; 543:564–567.
35.
DienzO, and RinconM. The effects of IL-6 on CD4 T cell responses. Clin Immunol, 2009; 130:27–33.
36.
DouekDC, McFarlandRD, KeiserPH, et al.Changes in thymic function with age and during the treatment of HIV infection. Nature, 1998; 396:690–695.
37.
EakleR, VenterF, and ReesH. Pre-exposure prophylaxis (PrEP) in an era of stalled HIV prevention: can it change the game?. Retrovirology, 2018; 15:29.
38.
EsterhazyD, LoschkoJ, LondonM, et al.Classical dendritic cells are required for dietary antigen-mediated induction of peripheral Treg cells and tolerance. Nat Immunol, 2016; 17:545–555.
39.
FarberDL, YudaninNA, and RestifoNP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol, 2014; 14:24–35.
40.
FonnerVA, DalglishSL, KennedyCE, et al.Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS, 2016; 30:1973–1983.
GanorY, RealF, SennepinA, et al.HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat Microbiol, 2019; 4:633–644.
43.
GeigerR, RieckmannJC, WolfT, et al.L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell, 2016; 167:829–842 e813.
44.
GerlachC, RohrJC, PerieL, et al.Heterogeneous differentiation patterns of individual CD8+ T cells. Science, 2013; 340:635–639.
45.
GriessingerCM, MaurerA, KesenheimerC, et al.64Cu antibody-targeting of the T-cell receptor and subsequent internalization enables in vivo tracking of lymphocytes by PET. Proc Natl Acad Sci U S A, 2015; 112:1161–1166.
46.
GrossmanZ, SinghNJ, SimonettiFR, et al.‘Rinse and Replace’: boosting T cell turnover to reduce HIV-1 reservoirs. Trends Immunol, 2020; 41:466–480.
47.
GuelerA, MoserA, CalmyA, et al.Life expectancy in HIV-positive persons in Switzerland: matched comparison with general population. Aids, 2017; 31:427–436.
48.
GulickRM, and FlexnerC. Long-acting HIV drugs for treatment and prevention. Annu Rev Med, 2019; 70:137–150.
49.
HazenbergMD, VerschurenMC, HamannD, et al.T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J Mol Med (Berl), 2001; 79:631–640.
50.
HiscottJ, KwonH, and GéninP. Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest, 2001; 107:143–151.
51.
HoYC, ShanL, HosmaneNN, et al.Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell, 2013; 155:540–551.
52.
HoneycuttJB, ThayerWO, BakerCE, et al.HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nat Med, 2017; 23:638–643.
53.
HosmaneNN, KwonKJ, BrunerKM, et al.Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J Exp Med, 2017; 214:959–972.
54.
HuangW, EshlemanSH, TomaJ, et al.Coreceptor Tropism in Human Immunodeficiency Virus Type 1 Subtype D: high Prevalence of CXCR4 tropism and heterogeneous composition of viral populations. J Virol, 2007; 81:7885–7893.
55.
ItanoAA, and JenkinsMK. Antigen presentation to naive CD4 T cells in the lymph node. Nat Immunol, 2003; 4:733–739.
56.
JakAF, YoshimuraA, MatsumotoA, et al.Letters to nature. Nature, 1997; 387:924–930.
57.
JamesonSC, and MasopustD. Understanding subset diversity in T cell memory. Immunity, 2018; 48:214–226.
58.
JolicoeurP. Murine acquired immunodeficiency syndrome (MAIDS): an animal model to study the AIDS pathogenesis. FASEB J, 1991; 5:2398–2405.
59.
KandathilAJ, SugawaraS, and BalagopalA. Are T cells the only HIV-1 reservoir?. Retrovirology, 2016; 13:86.
60.
KarpelME, BoutwellCL, and AllenTM. BLT humanized mice as a small animal model of HIV infection. Curr Opin Virol, 2015; 13:75–80.
61.
KimY, CameronPU, LewinSR, et al.Limitations of dual-fluorescent HIV reporter viruses in a model of pre-activation latency. J Int AIDS Soc, 2019; 22:e25425.
62.
KishtonRJ, SukumarM, and RestifoNP. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab, 2017; 26:94–109.
63.
KokYL, CiuffiA, and MetznerKJ. Unravelling HIV-1 latency, one cell at a time. Trends Microbiol, 2017; 25:932–941.
64.
KumarN, ChahroudiA, and SilvestriG. Animal models to achieve an HIV cure. Curr Opin HIV AIDS, 2016; 11:432–441.
65.
KunkelEJ, BoisvertJ, MurphyK, et al.Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes. Am J Pathol, 2002; 160:347–355.
66.
KuoHH, and LichterfeldM. Recent progress in understanding HIV reservoirs. Curr Opin HIV AIDS, 2018; 13:137–142.
67.
LaneBR, MarkovitzDM, WoodfordNL, et al.TNF-α inhibits HIV-1 replication in peripheral blood monocytes and alveolar macrophages by inducing the production of RANTES and decreasing C-C chemokine receptor 5 (CCR5) expression. J Immunol, 1999; 163:3653.
68.
LanzavecchiaA, and SallustoF. Regulation of T cell immunity by dendritic cells. Cell, 2001; 106:263–266.
69.
LauSY, WangP, MokBW, et al.Attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction. Emerg Microbes Infect, 2020; 9:837–842.
70.
LindqvistM, van LunzenJ, SoghoianDZ, et al.Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest, 2012; 122:3271–3280.
71.
MarbanC, ForouzanfarF, Ait-AmmarA, et al.Targeting the Brain Reservoirs: toward an HIV Cure. Front Immunol, 2016; 7:397.
72.
MelkusMW, EstesJD, Padgett-ThomasA, et al.Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med, 2006; 12:1316–1322.
73.
MilesB, and ConnickE. TFH in HIV latency and as sources of replication-competent virus. Trends Microbiol, 2016; 24:338–344.
74.
MurrayAJ, KwonKJ, FarberDL, et al.The Latent Reservoir for HIV-1: how immunologic memory and clonal expansion contribute to HIV-1 persistence. J Immunol, 2016; 197:407–417.
75.
NeidlemanJ, LuoX, FrouardJ, et al.Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir. Elife, 2020; 9:e60933.
76.
NixonCC, MavignerM, SilvestriG, et al.In vivo models of human immunodeficiency virus persistence and cure strategies. J Infect Dis, 2017; 215:S142–S151.
77.
NixonDE, and LandayAL. Biomarkers of immune dysfunction in HIV. Curr Opin HIV AIDS, 2010; 5:498–503.
78.
O'BrienM, ManchesO, and BhardwajN. Plasmacytoid dendritic cells in HIV infection. Adv Exp Med Biol, 2013; 762:71–107.
79.
OkoyeAA, and PickerLJ. CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev, 2013; 254:54–64.
80.
PasquereauS, KumarA, and HerbeinG. Targeting TNF and TNF receptor pathway in HIV-1 infection: from immune activation to viral reservoirs. Viruses, 2017; 9:64.
81.
PennockND, WhiteJT, CrossEW, et al.T cell responses: naive to memory and everything in between. Adv Physiol Educ, 2013; 37:273–283.
82.
PerezL, AndersonJ, ChipmanJ, et al.Evidence that CD32a does not mark the HIV-1 latent reservoir. Nature, 2018; 561:E20–E28.
83.
PietzschJ, GruellH, BournazosS, et al.A mouse model for HIV-1 entry. Proc Natl Acad Sci U S A, 2012; 109:15859–15864.
84.
PolicicchioBB, PandreaI, and ApetreiC. Animal models for HIV cure research. Front Immunol, 2016; 7:12.
85.
RezaeiSD, LuHK, ChangJJ, et al.The pathway to establishing HIV latency is critical to how latency is maintained and reversed. J Virol, 2018; 92:e02225-02217.
86.
RohJS, and SohnDH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw, 2018; 18:e27.
87.
RuaneD, BraneL, ReisBS, et al.Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J Exp Med, 2013; 210:1871–1888.
88.
RutsteinSE, SmithDK, DalalS, et al.Initiation, discontinuation, and restarting HIV pre-exposure prophylaxis: ongoing implementation strategies. Lancet HIV, 2020; 7:e721–e730.
89.
SachaJB, and NdhlovuLC. Strategies to target non-T-cell HIV reservoirs. Curr Opin HIV AIDS, 2016; 11:376–382.
90.
SallustoF. Heterogeneity of human CD4(+) T cells against microbes. Annu Rev Immunol, 2016; 34:317–334.
91.
SeayK, QiX, ZhengJH, et al.Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. PLoS One, 2013; 8:e63537.
92.
SebastianNT, and CollinsKL. Targeting HIV latency: resting memory T cells, hematopoietic progenitor cells and future directions. Expert Rev Anti Infect Ther, 2014; 12:1187–1201.
93.
SenguptaS, and SilicianoRF. Targeting the latent reservoir for HIV-1. Immunity, 2018; 48:872–895.
94.
SérorC, MelkiM-T, SubraF, et al.Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J Exp Med, 2011; 208:1823.
95.
SeungE, and TagerAM. Humoral immunity in humanized mice: a work in progress. J Infect Dis, 2013; 208Suppl 2:S155–S159.
96.
ShultzLD, BrehmMA, Garcia-MartinezJV, et al.Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol, 2012; 12:786–798.
97.
SilicianoJD, KajdasJ, FinziD, et al.Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+T cells. Nat Med, 2003; 9:727–728.
98.
Smith-GarvinJE, KoretzkyGA, and JordanMS. T cell activation. Annu Rev Immunol, 2009; 27:591–619.
99.
SpiegelH, HerbstH, NiedobitekG, et al.Rapid Communication Follicular Dendritic Cells Are a Major Reservoir for Human Immunodeficiency Virus Type 1 in Lymphoid Tissues Facilitating Infection of CD4 +. Am J Pathol, 1992; 140:15–22.
100.
SpinnerCD, BoeseckeC, ZinkA, et al.HIV pre-exposure prophylaxis (PrEP): a review of current knowledge of oral systemic HIV PrEP in humans. Infection, 2016; 44:151–158.
101.
TeiglerJE, LeyreL, ChomontN, et al.Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size. JCI Insight, 2018; 3:e98420.
102.
ThomeJJ, and FarberDL. Emerging concepts in tissue-resident T cells: lessons from humans. Trends Immunol, 2015; 36:428–435.
103.
TraggiaiE, ChichaL, MazzucchelliL, et al.Development of a human adaptive immune system in cord blood cell-transplanted mice. Science, 2004; 304:104.
104.
TuboNJ, PaganAJ, TaylorJJ, et al.Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell, 2013; 153:785–796.
105.
VanhamelJ, BruggemansA, and DebyserZ. Establishment of latent HIV-1 reservoirs: what do we really know?. J Virus Erad, 2019; 5:3–9.
106.
VansantG, BruggemansA, JanssensJ, et al.Block-and-lock strategies to cure HIV infection. Viruses, 2020; 12:84.
107.
Venanzi RulloE, CannonL, PinzoneMR, et al.Genetic evidence that naive T cells can contribute significantly to the human immunodeficiency virus intact reservoir: time to re-evaluate their role. Clin Infect Dis, 2019; 69:2236–2237.
108.
Venanzi RulloE, PinzoneMR, CannonL, et al.Persistence of an intact HIV reservoir in phenotypically naive T cells. JCI Insight, 2020; 5:e133157.
109.
VenturaJD, BeloorJ, AllenE, et al.Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice. PLoS Pathog, 2019; 15:e1008161.
110.
WangZ, GuruleEE, BrennanTP, et al.Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc Natl Acad Sci U S A, 2018; 115:E2575–E2584.
111.
WangZ, SimonettiFR, SilicianoRF, et al.Measuring replication competent HIV-1: advances and challenges in defining the latent reservoir. Retrovirology, 2018; 15:21.
112.
WeningerW, and von AndrianUH. Chemokine regulation of naive T cell traffic in health and disease. Semin Immunol, 2003; 15:257–270.
113.
WodarzD, and LevyDN. Pyroptosis, superinfection, and the maintenance of the latent reservoir in HIV-1 infection. Sci Rep, 2017; 7:3834.
114.
WongME, JaworowskiA, and HearpsAC. The HIV reservoir in monocytes and macrophages. Front Immunol, 2019; 10:1435.
115.
YangX, and GabuzdaD. Regulation of human immunodeficiency virus type 1 infectivity by the ERK mitogen-activated protein kinase signaling pathway. J Virol, 1999; 73:3460–3466.
116.
ZhangL, LiuS-H, WrightTT, et al.C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis. J Immunol, 2015; 194:5243.
