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Perspective on potential impact of HIV central nervous system latency on eradication

Chan, Phillipa; Ananworanich, Jintanata,b,c,d

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doi: 10.1097/QAD.0000000000002264
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Antiretroviral therapy (ART) has transformed HIV-1 infection from a life-threatening disease to a manageable yet sometimes complex chronic illness. Latent HIV-1 resides mostly in long-lived memory CD4+ T-lymphocytes in blood and lymphoid tissues, and poses a barrier to curing HIV-1. Reactivation of replication-competent virus in these cells can fuel a new round of cell infection in the absence of ART. HIV-1 cure is an important goal, given the challenges of lifelong ART adherence, the financial burden to healthcare systems, chronic immune activation [1,2], and non-AIDS related comorbidities including HIV-associated neurocognitive disorders (HAND) despite successful therapy [3–6].

The ultimate and nearly impossible goal of HIV-1 cure research is sterilizing cure or eradication, which aims to abolish all cells that harbor replication-competent provirus within the host cellular DNA. A functional cure or sustained virologic remission is a challenging yet more attainable goal. It is the ability to maintain plasma viral load below detection limit without ART despite the persistence of replication-competent HIV-1. The potential HIV-1 eradication in the Berlin patient and possibly, the London patient, required extreme means of cancer treatment and CCR5-negative stem cell transplantation [7–9]. Remission cases are unusual and mostly described in people who initiated ART during acute HIV-1 infection (AHI). There are several investigative approaches to reduce and control latently infected cells, namely, early ART, latency reactivation or suppression, and immune-based, cell-based and gene-editing therapies [10].

This article addresses three questions relating to the role of the HIV-1 central nervous system (CNS) latency on HIV-1 eradication. First, how is HIV-1 CNS infection and persistence relevant to HIV-1 cure efforts? Second, how do HIV-1 remission strategies affect the CNS? Third, what future investigations could be considered in HIV-1 remission studies?

How is HIV-1 central nervous system infection and persistence relevant to HIV-1 cure efforts?

HIV-1 clearly involves the CNS. Millions living with HIV-1 suffer from HAND that affects their lives in substantial ways. Although ART has dramatically reduced HIV-associated dementia, milder forms of HAND are prevalent in 15–55% of people with HIV [4,5,11]. Moreover, new onset and ongoing deterioration of cognitive impairment occur despite ART [6,12,13]. HIV-1 RNA is readily detected in cerebrospinal fluid (CSF) samples within days of infection [14,15]. Even under viral suppression with ART, some individuals have elevated soluble inflammatory biomarkers in the CSF [16]. Microglial activation on PET can also be observed in treated individuals and is associated with lower cognitive performance [17].

Whether the HIV-1 virions in the CNS are replication-competent is unproven. However, some treated individuals with plasma viral suppression have low levels of HIV-1 RNA in their CSF [18]. In the systemic circulation, infected CD4+ T-lymphocytes with defective HIV-1 DNA generate incomplete RNA transcripts that contribute to persistent immune activation [19,20]. Future studies should clarify if such phenomenon co-exists in the CNS as HIV-1 DNA is frequently present in the brain cells of people who have been on years of suppressive ART [21].

Controlling CNS infection and persistence is integral to the efforts in curing HIV-1. First, HIV-1 remission strategies should reduce frequencies of HIV-infected cells in the CNS. HIV-1-infected brain cells are long lived residential cells including perivascular macrophages, microglia and astrocytes. Pathological studies suggest their ability to harbor HIV-1 DNA with or without the development of HIV encephalitis [22–27], and the frequencies of HIV-1 DNA+ cells correlate with reduced cognitive function [28,29]. Despite long-term suppressive ART, brain macrophages/microglia from simian immunodeficiency virus (SIV)-infected macaques still harbor replication-competent virus that could be reactivated by latency-reversing agents (LRA) [30,31].

Second, strategies should improve control of viral replication in the CNS. CNS viral escape is when HIV-1 RNA is detected only in the CSF, or CSF viremia is at least 1log10copies/ml above a fairly well controlled HIV-1 RNA in blood [32–34]. Although mostly asymptomatic, CNS viral escape is linked to elevated CSF soluble inflammatory markers [18,33,35]. Moreover, patients with symptomatic CNS viral escape can present with a spectrum of neurologic issues ranging from a mild headache or sensory disturbance to encephalopathy or coma [36–38]. Symptomatic viral escape typically responds to ART adjustment guided by genotyping of CSF HIV-1, or by selecting ART regimens with higher CNS penetration-effectiveness (CPE) scores [36,39]. However, the latter does not necessarily improve the cognitive outcome of individuals with HAND [40–42]. Furthermore, studies have reported ART-resistant strains in the CSF of treated individuals with plasma viral suppression [36,38,39].

Third, remission strategies should target viral quasispecies that may be different in CSF compared with blood. HIV-1 CNS compartmentalization can occur as early as the first year of infection in untreated individuals [43]. In one report, HIV-1 CNS compartmentalization persists during ART and returns during viral rebound post-ART interruption [44]. The repertoires of HIV-specific CD8+ T-lymphocyte receptors are different between CSF and blood even at AHI [45]. Such phenomenon could affect the responses to immune-based HIV-1 remission strategy.

How do HIV remission and cure strategies affect the central nervous system?

Table 1 summarizes human and nonhuman primate (NHP) studies that evaluate the CNS outcomes of stand-alone treatment interruptions and remission strategies with or without treatment interruptions .

Table 1
Table 1:
Neurological outcomes in treatment interruption and remission intervention studies.

Early antiretroviral therapy

ART initiated during AHI markedly reduces frequencies of cells that harbor HIV-1 DNA in blood and lymphoid tissues [46,47], and associates with higher CD4+ T lymphocytes and CD4+/CD8+ ratio [48]. Compared with ART initiation at chronic infection, early ART leads to lower levels of CSF microglial activation [49] and neuronal damage markers [50], and normalization of intracranial inflammation in magnetic resonance spectroscopy (MRS) studies [51,52]. People received early ART (20–132 estimated days of exposure) also have markedly reduced CSF HIV-1 antibody levels likely because of shorter HIV-1 antigen exposure [53]. In short, early ART initiation could contribute to a dramatic reduction in systemic, and likely, CNS reservoirs. Together with the preserved adaptive immunity, early treated individuals could be better candidates for HIV-1 remission strategies.

Latency reversal agents

Latency reversal is part of the ‘shock and kill’ concept [54]. It aims to ‘shock’ infected cells out of latency, forcing them to express viral antigens and thereby exposing them to killing by direct viral cytopathic action and HIV-specific cytotoxic T-lymphocytes (CTLs). Early trials combining anti-CD3 antibody and recombinant human IL-2 that induced global T-lymphocyte activation validated the concept of latency reversal but also induced significant toxicity from cytokine release [55,56]. Subsequent research has focused on small molecule LRAs that do not cause overt T-lymphocytes activation and cytokine release [57].

Such LRAs include histone deacetylation inhibitors (HDACi) that block the epigenetic control of proviral gene silencing (e.g. vorinostat, panobinostat and romidepsin); protein kinase C (PKC) agonists that induce transcription factor NF-κB (e.g. prostratin, bryostatin-1, and ingenol compounds); and toll-like receptor (TLR) agonists that reactivate viral latency through cellular signaling [58,59].

Most LRAs appear to be nontoxic to primary CNS cells at therapeutic concentrations [60]. Some LRAs, including romidepsin, JQ-1, and panobinostat, can induce viral transcription in infected astrocytes in vitro[60–62]. One study shows bryostatin-1 to reactivate infected astrocytes with p24 antigen upregulation [62] and yet another LRA study shows bryostatin-1 fails to reactivate the latency of infected astrocytes after initial active viral productive phase [63]. In-vitro macrophage/microglia studies demonstrate that combination of LRA reactivates latent virus with increased HIV-1 mRNA and protein levels [64,65].

Non-human primate (NHP) studies provide insight into the viral dynamics of the HIV-1 reservoir in the CNS. After administration Ingenol-B and vorinostat, one out of two SIV-infected macaques on long-term suppressive ART developed SIV encephalitis with neurological symptoms; subsequent CSF examination showed a viral load 10-fold higher than that in plasma [30]. Postnecropsy investigations suggest that the CSF viral transcripts originate from resident CD68+ macrophages/microglia within the occipital lobe of the brain. Importantly, replication-competent virus was isolated from infected brain macrophages in seven out of eight macaques under similar experimental conditions [31]. Therefore, a balance between CNS-desired effects and safety requires careful consideration.

More than 15 clinical trials have evaluated LRAs, and some showed a modest increase in blood cell-associated and plasma HIV RNA after LRAs without a decrease in cell-associated HIV DNA [59]. Two assessed the CNS outcomes and showed no adverse effects [66,67]. One panobinostat study exhibited undetectable CSF HIV-1 RNA in 11 participants despite six having measurable plasma HIV-1 RNA after the last dose of LRA [68]. There were also no changes in CSF inflammatory and neuronal injury markers. Perhaps these findings are unsurprising given the undetectable CSF levels of panobinostat. Our group previously examined the effect of vorinostat, hydroxychloroquine and maraviroc (VHM) in 10 acutely treated AHI participants who have maintained viral suppression for at least 48 weeks [67]. VHM was given under ART coverage, followed by ART interruption. Low-grade CSF HIV-1 viremia was detected in two out of eight CSF samples (25 and 42 copies/ml) at systemic viral rebound (plasma HIV RNA 25796 and 329 copies/ml respectively) after treatment interruptions . There was no adverse CNS outcome observed from serial neuropsychiatric tests, CSF inflammatory markers measurements and MRS.

Multiple factors could affect the outcomes of LRAs. Apart from CNS penetration, LRAs may alter the blood–brain barrier (BBB) permeability and immune cell functions [69]. Moreover, inconsistent reactivation responses [61] and LRAs-induced reactivation of defective HIV-1 provirus reservoir [20,70] may hinder the efficacy of subsequent killing of the ‘true’ reservoir.

Latency suppression agents

The improved understanding of HIV-1 latency also gives rise to the ‘block and lock’ strategy that aims to disarm the reactivation ability of the HIV-1 reservoir. HIV-1 transactivator of transcription (Tat) protein, which expresses early in the viral life cycle and promotes subsequent HIV transcription, appears to be a potential target for intervention because of the absence of a human homolog. Didehydro-cortistatin A (dCA) is an analog of the natural compound cortistatin A. It potently inhibits Tat production from infected CD4+ T-lymphocytes isolated from viraemic and aviraemic patients [71]. In combination with ART, dCA potentiates the inhibition of viral production during cellular expansion in comparison to ART alone [72]. dCA further inhibits viral reactivation in T-lymphocytes exposed to LRAs and ART interruption [72,73]. dCA crosses the BBB in animal models and inhibits Tat uptake in microglia-like and astrocytes cell lines [74].

In the CNS, Tat may directly contribute to HAND through pro-inflammatory and direct cytotoxic effects [75]. Tat induces neurobehavioral deleterious effects in an animal model [76]. It upregulates platelet-derived growth factor in astrocytes [77], which eventually leads to CCL2 secretion and monocyte infiltration across BBB [78]. It may also cause direct neuronal loss through astrocytosis-related excitotoxicity [79]. As a result, if dCA shows a similar inhibition of latency reactivation in CNS-infected cells, it may alleviate intracerebral immune activation and perhaps offer a viable alternative for HIV remission.

Immune-based therapies

Aside from the complexity of the CNS response during ‘shock,’ the lack of an effective ‘kill’ mechanism marks another major obstacle to a cure. Human and NHP trials have evaluated interventions to enhance antibody and T-cell functions. Their mechanisms and study outcomes were recently reviewed [80].

Broadly neutralizing antibodies

Broadly neutralizing antibodies (bNAbs) can neutralize diverse, multiclade, circulating HIV-1 strains. BNAbs bind cell-free virus, block new infection [81], and reduce infected cells through Fcυ receptor-dependent mechanisms in animal models [82]. The effect of bNAbs in CNS is unclear. First, bNAbs are theoretically too large to cross the BBB and gain access to locally infected cells. Second, bNAbs may not target virus-containing compartments in monocyte-derived macrophages according to in-vitro experiments [83,84]. Antibody-treated macrophages remain infectious and could transmit HIV-1 to CD4+ T lymphocytes via macrophage-T-lymphocytes virological synapse [83,85]. The role of bNAbs in reducing infection in microglia and astrocytes requires further studies. Our group did not observe changes in neuropsychological tests or MRI parameters in acutely treated participants who either received VRC01 bNAb or placebo at the time of treatment interruptions [86]. A subset with CSF samples did not reveal viremia posttreatment interruptions despite detectable plasma viremia [86,87].

Antiα4β7 integrin Ab

α4β7 integrin is a gut-homing receptor and target of HIV-1 gp120 [88,89]. It is extensively expressed on memory CD4+ T-lymphocytes [90], resulting in massive infection and depletion of gut α4β7+ CD4+ T lymphocytes during productive HIV-1 infection. Sustained SIV remission has been reported in macaques treated with primatized α4β7 integrin monoclonal antibody (mAb) in addition to ART during primary infection [91]. Vedolizumab, an approved α4β7 integrin mAb treatment for inflammatory bowel diseases, is being investigated for HIV remission in chronically HIV-infected people (NCT02788175 and NCT03147859). Vedolizumab does not affect T-lymphocyte migration to the CNS like the α4β1 mAb (Natalizumab) [92]. Although vedolizumab is not anticipated to impact CNS immune surveillance and cause neurologic diseases, CNS safety monitoring is prudent as being performed in one study (NCT03147859).

T lymphocyte-enhancing strategies

Boosting T-lymphocyte immunity against HIV-infected cells is another killing strategy. Learning from the cancer field, several agents including dual affinity retargeting molecules (DARTs), immune checkpoint inhibitors and therapeutic vaccines are now being investigated for HIV-1 infection.

DARTs are bispecific, antibody-based molecules that recognize two different epitopes and redirect T cells to target cells [93]. Applications of DARTs in hematological malignancies are actively explored [94], but little is known about their effects on the CNS residential cells including macrophages, microglia and astrocytes.

Immune checkpoint inhibitors aim to reverse the immune exhaustion and dysfunction of HIV-specific CD8+ T-lymphocytes during chronic HIV-1 infection. Antiprogrammed death ligand 1 (PD-L1) mAb was well tolerated in a phase 1 trial involving eight HIV-1 infected individuals on suppressive ART [95] but one developed asymptomatic hypophysitis 266 days after the infusion. Endocrine complications including hypophysitis and hypothyroidism/thyroiditis are observed in cancer trials with immune checkpoint inhibitors, such as anticytotoxic T-lymphocyte-associated molecule 4 (8 and 6%, respectively, n = 256) [96], and to a lesser extent, anti-PD-L1 [97]. Neurological complications such as myopathy, neuropathies and cerebellar ataxia were reported in 2.9% of cancer patients (n = 347) who received anti-PD-L1 mAb [98]. Given these infrequent but severe toxicities, close systemic and CNS monitoring is warranted in trials using immune checkpoint inhibitors.

Therapeutic vaccinations induce systemic immune responses against target cells including brain cells. Dendritic cell-based vaccines show promising results in cancer trials of CNS glioma and glioblastoma [99,100]. Severe immune-related toxicity is less frequent in dendritic cell vaccines compared with antibody-based treatment for cancers [99]. HIV-1 antigen-pulsed dendritic cell vaccines can induce HIV-specific T-lymphocytes responses in HIV-infected individuals on suppressive ART [101]. Boosted dendritic cells may also reactivate latent HIV-1 provirus [102,103]. In one study, 4 out of 10 participants on ART had a transient increase in plasma HIV-1 RNA levels following autologous dendritic cell vaccines [104]. Although the vaccination did not prevent viral rebound during ART interruption, it showed a modest reduction in peak plasma viremia [104]. Other therapeutic HIV-1 vaccine combinations, such as ChAdV63.HIVcons and MVA.HIVconsv showed potential in viremic control potential among participants who started ART within first year of HIV-1 infection [105].

The chimeric antigen receptor (CAR) engineered T-lymphocytes offer a new option for difficult-to-treat cancers and possibly HIV-1. FDA-approved CD19-targeted CAR-T therapy in 2017 for relapsed or refractory B-cell acute lymphoblastic leukemia and lymphoma. First generation CAR-T therapy for HIV used CD8+ T cells CAR expressing CD4+ infused with a CD3+ zeta-signaling domain. It showed good safety profile and partial effect on plasma viremia [106–108]. Second generation CAR-T therapy is based on bNAb expression to enhance specific killing of infected cells, and disruption of CCR5 to reduce cell infectivity [109]. Primary human T-cell model of bNAb CARs shows elimination of HIV-infected CD4+ T lymphocytes in the absence of active viral replication [109]. The induced mutation of CCR5 locus protects these CAR-T cells from HIV-1 infection [109]. Phase I/II CAR-T study in chronically HIV-infected individuals is ongoing (NCT03240328). Toxicities are less likely to happen in HIV-infected individuals than in cancer patients as they have large tumor burden and hence a higher risk of cytokine releasing syndrome [110]. The incidence of neurotoxicity in cancer settings ranges from 0 to 50% [111]. Their manifestations are diverse and nonlocalizing, including headaches, confusion, and occasionally life-threatening convulsions [111].

Taken together, both antibody-based and T-lymphocyte-enhancing strategies offer compelling evidence to decrease HIV-1 reservoirs and promote virologic remission [82,91,112,113]. The potential for antibodies to affect CNS viral latency is uncertain given their general lack of CNS penetration. Enhanced T-lymphocytes could readily cross the BBB and perhaps target the infected CNS cells. Whether they are beneficial in eliminating HIV-infected cells in the CNS remains to be clarified. Regardless, the extent and duration of such T-lymphocyte-driven cytotoxicity need monitoring.

What future investigations could be considered in HIV remission studies?

There are two primary goals to perform CNS investigations in HIV remission studies. First is to determine whether experimental agents and treatment interruptions are well tolerated. Second is to understand the effects of remission interventions on CNS HIV persistence.

Experimental agents in HIV remission trials can have direct or indirect effects on the CNS. Those that cross the BBB may reactivate or kill target-infected cells resulting in localized immune activation. The systemic effects of agents that do not cross BBB could indirectly affect the CNS through systemic viremia and immune activation. Treatment interruption is included in remission trials to measure the efficacy of interventions because there are no biomarkers for posttreatment control. Short treatment interruptions with frequent HIV-1 RNA monitoring have been proven to be clinically safe [67,86,114], but severe complications could occur in rare cases. Both Boston patients with CCR5+ allogeneic stem cell transplantation from HIV-uninfected donors had low-level CSF viremia during systemic viral rebound posttreatment interruptions, but one subsequently developed HIV-meningitis [115]. The lack of preexisting HIV-1 immunity likely contributed to the meningitis. Furthermore, life-threatening encephalitis secondary to massive immune activation and CD8+ T-lymphocyte infiltration can occur after CNS viral escape in unplanned treatment interruptions [116], highlighting the crucial role of CNS monitoring in remission studies.

We propose CNS monitoring based on our experience conducting four HIV-1 remission trials with treatment interruptions at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand.

All participants initiated ART during AHI and sustained at least 12 months of viral suppression before entering the remission trials, which included shock and kill (NCT02475915, n = 14), VRC01 bNAb infusion (NCT03036709, n = 18), and very early ART initiation in Fiebig 1 AHI (NCT02614950, n = 8). Plasma viral load was monitored every 3–7 days in these trials. ART was resumed for confirmed plasma viral load greater than 1000 copies/ml, fall in CD4+ T-lymphocyte count, development of clinical HIV disease or acute retroviral syndrome, pregnancy, or at volunteer request. No participant experienced severe neurological adverse events or change in cognitive function as a result of interventions and treatment interruptions . CSF viremia and elevated inflammatory markers during ATI were uncommon despite detectable plasma viremia [67,86,114].

HIV remission studies should incorporate clinical neurologic monitoring at a minimum. This includes self-reported questionnaires, standardized neurological examination, and neuropsychological testing. Serial CSF sampling before and after intervention as well as after treatment interruptions is ideal but may not be acceptable to some participants. The most important sampling time-point depends on the intervention and the research question. In LRA trials, CSF sampling shortly after serial LRA dosing when maximum activity is expected would be informative to understand possibly deleterious CNS effects from viral activation. In people who achieve remission post treatment interruptions, CSF sampling during plasma viral suppression off ART maybe helpful to understand if viral escape has occurred. In immune interventional trials with long treatment interruptions, CSF sampling could be done after plasma viral set-point or at the time point prior to ART resumption to understand if the rebound virus in the blood vs. the CSF are phylogenetically different; therefore, compartmentalized. Measurement of immune markers in both plasma and CSF samples would help to clarify whether people in remission have heightened immune activation similar to elite controllers, which is linked to unfavorable clinical outcomes [117,118] and cognitive decline in neurodegenerative diseases [119]. Plasma and CSF neurofilament light chain protein (NFL) assay could provide additional information for subclinical neuronal damage [120].

Neuroimaging could be used for neurological monitoring given the noninvasiveness and likely superior sensitivity for preclinical changes. MRI sequences, such as MRS and diffusion-tensor imaging (DTI) are useful to detect intracerebral inflammation and microstructure change, respectively. Another potential MRI technique includes diffusion basis spectrum imaging (DBSI), which provides paired axonal integrity and pathological information through additional evaluation of vasogenic edema and cellularity [121,122].

Figure 1 illustrates the proposed CNS data acquisition at different phases of a remission study: preintervention preparation: document baseline neurologic functions, neuroimaging, CSF viremia, immune activation markers and viral sequences, during and postintervention: assess changes from baseline for clinical and laboratory markers, measure concentration of experimental agents if appropriate, posttreatment interruptions: evaluate neurologic functions for safety, and measure CSF viremia and inflammatory markers in individuals who experience plasma viral load rebound, and in those with sustained aviremia. Phylogenetic analysis can be performed in CSF viremic individuals to compare with pre-ART or baseline sequences, which will inform the source of rebound viremia and possible selective immune pressure from interventions, and post-ART resumption and viral resuppression: safety monitoring to ensure that any neuropsychiatric manifestations, CSF viremia, and inflammation normalizes or return to baseline values.

Fig. 1
Fig. 1:
Central nervous system monitoring in cure studies.Top row: different phase of cure studies. Middle row: information of interest to better understand CNS latency and intervention effect. Lower row: modalities of CNS assessment. CNS, central nervous system.

Given the multisystem involvement of HIV and the impracticability of multitissue sampling (especially the brain) for disease evaluation, priority should be given to developing noninvasive methods to measure HIV disease activity. Molecular imaging using PET has been increasingly used in HIV research. An immuno-PET study in SIV-infected monkeys used 64Cu-labeled SIV Gp120-specific antibody ligand to locate infected cells throughout the body except the brain because the antibody did not penetrate the BBB [123]. PET imaging based on 18 kDA translocator protein (TPSO)-targeted ligand measures activation of microglia activation and has become a valid choice for neuroinflammation research [17,124]. Vascular PET that evaluates atherosclerotic vascular inflammation [125,126] could be helpful for predicting long-term comorbidities. Dual-tracer PET imaging [127] in HIV infection should be explored given its success in cancer research.


HIV persistence in the CNS is an obstacle to curing HIV. Strategies towards a remission and cure should reduce the frequencies of HIV-infected cells, improve control of viral replication and target unique viral quasispecies within the CNS. HIV remission trials include experimental agents and treatment interruptions that can directly and indirectly impact the CNS, but CNS monitoring is often not done. Latency-modifying agents, therapeutic vaccines and cell-based therapies can cross the BBB, and potentially target infected cells resulting in local immune activation. Antibody-based therapies generally do not cross the BBB but its systemic effects on viremia and immune activation could affect the CNS. Therefore, HIV remission studies should incorporate CNS investigations to determine if experimental agents and treatment interruptions are safe, and to understand the effects of interventions on CNS HIV persistence.


We thank Drs Serena Spudich, Eugene Kroon, and Donn Colby for the helpful discussions and advice on this article, Ms. Ellen Turk for editorial assistance and Ms. Oratai Butterworth for administrative support. J.A. was funded in part by the U.S. National Institute of Health (R01NS084911-01 and UM1AI126603).

Disclaimer: The views and opinions expressed in the article are solely those of the authors and are not intended to represent those of the US Army or the Department of Defense, or the National Institutes of Health, Department of Health and Human Services, USA.

Conflicts of interest

P.C. declares no conflict of interest. J.A. has participated in advisory boards for ViiV Healthcare and Gilead, and meetings for Merck, and served as a consultant for Roche and AbbVie.


1. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet 2013; 382:1525–1533.
2. Tsoukas C. Immunosenescence and aging in HIV. Curr Opin HIV AIDS 2014; 9:398–404.
3. Longenecker CT, Sullivan C, Baker JV. Immune activation and cardiovascular disease in chronic HIV infection. Curr Opin HIV AIDS 2016; 11:216–225.
4. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69:1789–1799.
5. Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, et al. CHARTER GroupHIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010; 75:2087–2096.
6. Heaton RK, Franklin DR Jr, Deutsch R, Letendre S, Ellis RJ, Casaletto K, et al. CHARTER GroupNeurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis 2015; 60:473–480.
7. Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 2011; 117:2791–2799.
8. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; 360:692–698.
9. Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D, Salgado M, et al. HIV-1 remission following CCR5Delta32/Delta32 haematopoietic stem-cell transplantation. Nature 2019; 568:244–248.
10. Deeks SG, Lewin SR, Ross AL, Ananworanich J, Benkirane M, Cannon P, et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med 2016; 22:839–850.
11. Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 2007; 21:1915–1921.
12. Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, et al. CHARTER GroupAsymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 2014; 82:2055–2062.
13. Sacktor N, Skolasky RL, Seaberg E, Munro C, Becker JT, Martin E, et al. Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology 2016; 86:334–340.
14. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, et al. RV254/SEARCH 010 Study GroupCentral nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 2012; 206:275–282.
15. Chan P, Patel P, Hellmuth J, Colby DJ, Kroon E, Sacdalan C, et al. RV254/SEARCH 010 Study TeamDistribution of HIV RNA in CSF and Blood is linked to CD4/CD8 Ratio During Acute HIV. J Infect Dis 2018; 218:937–945.
16. Yilmaz A, Yiannoutsos CT, Fuchs D, Price RW, Crozier K, Hagberg L, et al. Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 2013; 10:62.
17. Vera JH, Guo Q, Cole JH, Boasso A, Greathead L, Kelleher P, et al. Neuroinflammation in treated HIV-positive individuals: A TSPO PET study. Neurology 2016; 86:1425–1432.
18. Dahl V, Peterson J, Fuchs D, Gisslen M, Palmer S, Price RW. Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 2014; 28:2251–2258.
19. Imamichi H, Dewar RL, Adelsberger JW, Rehm CA, O’Doherty U, Paxinos EE, et al. Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. Proc Natl Acad Sci U S A 2016; 113:8783–8788.
20. Pollack RA, Jones RB, Pertea M, Bruner KM, Martin AR, Thomas AS, et al. Defective HIV-1 proviruses are expressed and can be recognized by cytotoxic T lymphocytes, which shape the proviral landscape. Cell Host Microbe 2017; 21:494.e4–506.e4.
21. Lamers SL, Rose R, Maidji E, Agsalda-Garcia M, Nolan DJ, Fogel GB, et al. HIV DNA is frequently present within pathologic tissues evaluated at autopsy from combined antiretroviral therapy-treated patients with undetectable viral loads. J Virol 2016; 90:8968–8983.
22. Thompson KA, Cherry CL, Bell JE, McLean CA. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol 2011; 179:1623–1629.
23. Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson RT, Glass JD. Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol 1996; 39:705–711.
24. An SF, Groves M, Giometto B, Beckett AA, Scaravilli F. Detection and localisation of HIV-1 DNA and RNA in fixed adult AIDS brain by polymerase chain reaction/in situ hybridisation technique. Acta Neuropathol 1999; 98:481–487.
25. Crowe S, Zhu T, Muller WA. The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection. J Leukoc Biol 2003; 74:635–641.
26. Chen NC, Partridge AT, Sell C, Torres C, Martin-Garcia J. Fate of microglia during HIV-1 infection: from activation to senescence?. Glia 2017; 65:431–446.
27. Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DF, et al. Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol 2006; 12:146–152.
28. Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, et al. Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 2013; 80:1415–1423.
29. Gelman BB, Lisinicchia JG, Morgello S, Masliah E, Commins D, Achim CL, et al. Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort. J Acquir Immune Defic Syndr 2013; 62:487–495.
30. Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, et al. LRA-SIV Study GroupReactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS 2017; 31:5–14.
31. Avalos CR, Abreu CM, Queen SE, Li M, Price S, Shirk EN, et al. Brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir. MBio 2017; 8: pii: e01186-17.
32. Eden A, Marcotte TD, Heaton RK, Nilsson S, Zetterberg H, Fuchs D, et al. Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One 2016; 11:e0157160.
33. Eden A, Fuchs D, Hagberg L, Nilsson S, Spudich S, Svennerholm B, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis 2010; 202:1819–1825.
34. Joseph J, Cinque P, Colosi D, Dravid A, Ene L, Fox H, et al. Highlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA. J Virus Erad 2016; 2:243–250.
35. Eden A, Nilsson S, Hagberg L, Fuchs D, Zetterberg H, Svennerholm B, et al. Asymptomatic cerebrospinal fluid HIV-1 viral blips and viral escape during antiretroviral therapy: a longitudinal study. J Infect Dis 2016; 214:1822–1825.
36. Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 2012; 26:1765–1774.
37. Canestri A, Lescure FX, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis 2010; 50:773–778.
38. Bingham R, Ahmed N, Rangi P, Johnson M, Tyrer M, Green J. HIV encephalitis despite suppressed viraemia: a case of compartmentalized viral escape. Int J STD AIDS 2011; 22:608–609.
39. Beguelin C, Vazquez M, Bertschi M, Yerly S, de Jong D, Rauch A, Cusini A. Viral escape in the CNS with multidrug-resistant HIV-1. J Int AIDS Soc 2014; 17: (4 Suppl 3): 19745.
40. Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS 2011; 25:357–365.
41. Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 2009; 23:1359–1366.
42. Tozzi V, Balestra P, Salvatori MF, Vlassi C, Liuzzi G, Giancola ML, et al. Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders. J Acquir Immune Defic Syndr 2009; 52:56–63.
43. Sturdevant CB, Joseph SB, Schnell G, Price RW, Swanstrom R, Spudich S. Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. PLoS Pathog 2015; 11:e1004720.
44. Gianella S, Kosakovsky Pond SL, Oliveira MF, Scheffler K, Strain MC, De la Torre A, et al. Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy. Virus Evol 2016; 2:vew020.
45. Kessing CF, Spudich S, Valcour V, Cartwright P, Chalermchai T, Fletcher JL, et al. High number of activated CD8+ T cells targeting HIV antigens are present in cerebrospinal fluid in acute HIV infection. J Acquir Immune Defic Syndr 2017; 75:108–117.
46. Ananworanich J, Chomont N, Eller LA, Kroon E, Tovanabutra S, Bose M, et al. RV217 and RV254/SEARCH010 study groupsHIV DNA set point is rapidly established in acute HIV infection and dramatically reduced by early ART. EBioMedicine 2016; 11:68–72.
47. Ananworanich J, Chomont N, Fletcher JL, Pinyakorn S, Schuetz A, Sereti I, et al. Markers of HIV reservoir size and immune activation after treatment in acute HIV infection with and without raltegravir and maraviroc intensification. J Virus Erad 2015; 1:116–122.
48. Ananworanich J, Sacdalan CP, Pinyakorn S, Chomont N, de Souza M, Luekasemsuk T, et al. Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection. J Virus Erad 2016; 2:43–48.
49. Peluso MJ, Valcour V, Phanuphak N, Ananworanich J, Fletcher JL, Chalermchai T, et al. RV254SEARCH 010, RV304SEARCH 013, and SEARCH 011 Study TeamsImmediate initiation of cART is associated with lower levels of cerebrospinal fluid YKL-40, a marker of microglial activation, in HIV-1 infection. AIDS 2017; 31:247–252.
50. Peluso MJ, Valcour V, Ananworanich J, Sithinamsuwan P, Chalermchai T, Fletcher JL, et al. RV254/SEARCH 010 and SEARCH 011 Study TeamsAbsence of cerebrospinal fluid signs of neuronal injury before and after immediate antiretroviral therapy in acute HIV infection. J Infect Dis 2015; 212:1759–1767.
51. Sailasuta N, Ross W, Ananworanich J, Chalermchai T, DeGruttola V, Lerdlum S, et al. RV254/SEARCH 010 protocol teamsChange in brain magnetic resonance spectroscopy after treatment during acute HIV infection. PLoS One 2012; 7:e49272.
52. Young AC, Yiannoutsos CT, Hegde M, Lee E, Peterson J, Walter R, et al. Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection. Neurology 2014; 83:1592–1600.
53. Burbelo PD, Price RW, Hagberg L, Hatano H, Spudich S, Deeks SG, et al. Anti-human immunodeficiency virus antibodies in the cerebrospinal fluid: evidence of early treatment impact on central nervous system reservoir?. J Infect Dis 2018; 217:1024–1032.
54. Margolis DM, Garcia JV, Hazuda DJ, Haynes BF. Latency reversal and viral clearance to cure HIV-1. Science 2016; 353:aaf6517.
55. Fraser C, Ferguson NM, Ghani AC, Prins JM, Lange JM, Goudsmit J, et al. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS 2000; 14:659–669.
56. Prins JM, Jurriaans S, van Praag RM, Blaak H, van Rij R, Schellekens PT, et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 1999; 13:2405–2410.
57. Yang HC, Xing S, Shan L, O’Connell K, Dinoso J, Shen A, et al. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J Clin Invest 2009; 119:3473–3486.
58. Margolis DM, Archin NM. Proviral latency, persistent human immunodeficiency virus infection, and the development of latency reversing agents. J Infect Dis 2017; 215: (Suppl 3): S111–S118.
59. Spivak AM, Planelles V. Novel latency reversal agents for HIV-1 cure. Annu Rev Med 2018; 69:421–436.
60. Gray LR, On H, Roberts E, Lu HK, Moso MA, Raison JA, et al. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells. J Neurovirol 2016; 22:455–463.
61. Gray LR, Cowley D, Welsh C, Lu HK, Brew BJ, Lewin SR, et al. CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies. Mol Psychiatry 2016; 21:574–584.
62. Diaz L, Martinez-Bonet M, Sanchez J, Fernandez-Pineda A, Jimenez JL, Munoz E, et al. Bryostatin activates HIV-1 latent expression in human astrocytes through a PKC and NF-kB-dependent mechanism. Sci Rep 2015; 5:12442.
63. Barat C, Proust A, Deshiere A, Leboeuf M, Drouin J, Tremblay MJ. Astrocytes sustain long-term productive HIV-1 infection without establishment of reactivable viral latency. Glia 2018; 66:1363–1381.
64. Castellano P, Prevedel L, Eugenin EA. HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Sci Rep 2017; 7:12866.
65. Darcis G, Kula A, Bouchat S, Fujinaga K, Corazza F, Ait-Ammar A, et al. An In-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+JQ1 and ingenol-B+JQ1 to potently reactivate viral gene expression. PLoS Pathog 2015; 11:e1005063.
66. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV 2014; 1:e.13–e.21.
67. Kroon E, Ananworanich J, Le L, Intasan J, Benjapornpong K, Pinyakorn S, et al. Central nervous system impact of vorinostat, hydroxychloroquine and maraviroc combination therapy followed by treatment interruption in individuals treated during acute HIV infection (SEARCH 026) In: IAS; 2016.
68. Rasmussen TA, Tolstrup M, Moller HJ, Brinkmann CR, Olesen R, Erikstrup C, et al. Activation of latent human immunodeficiency virus by the histone deacetylase inhibitor panobinostat: a pilot study to assess effects on the central nervous system. Open Forum Infect Dis 2015; 2:ofv037.
69. Dental C, Proust A, Ouellet M, Barat C, Tremblay MJ. HIV-1 latency-reversing agents prostratin and bryostatin-1 induce blood-brain barrier disruption/inflammation and modulate leukocyte adhesion/transmigration. J Immunol 2017; 198:1229–1241.
70. Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med 2016; 22:1043–1049.
71. Mousseau G, Clementz MA, Bakeman WN, Nagarsheth N, Cameron M, Shi J, et al. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe 2012; 12:97–108.
72. Kessing CF, Nixon CC, Li C, Tsai P, Takata H, Mousseau G, et al. In vivo suppression of HIV rebound by didehydro-cortistatin A, a ‘block-and-lock’ strategy for HIV-1 treatment. Cell Rep 2017; 21:600–611.
73. Mousseau G, Kessing CF, Fromentin R, Trautmann L, Chomont N, Valente ST. The tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency. MBio 2015; 6:e00465.
74. Mediouni S, Jablonski J, Paris JJ, Clementz MA, Thenin-Houssier S, McLaughlin JP, et al. Didehydro-cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice. Curr HIV Res 2015; 13:64–79.
75. Zayyad Z, Spudich S. Neuropathogenesis of HIV: from initial neuroinvasion to HIV-associated neurocognitive disorder (HAND). Curr HIV/AIDS Rep 2015; 12:16–24.
76. Moran LM, Fitting S, Booze RM, Webb KM, Mactutus CF. Neonatal intrahippocampal HIV-1 protein Tat(1-86) injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation. Int J Dev Neurosci 2014; 38:195–203.
77. Bethel-Brown C, Yao H, Hu G, Buch S. Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation. J Neuroinflammation 2012; 9:262.
78. Tewari M, Monika, Varghse RK, Menon M, Seth P. Astrocytes mediate HIV-1 Tat-induced neuronal damage via ligand-gated ion channel P2X7R. J Neurochem 2015; 132:464–476.
79. Shin AH, Kim HJ, Thayer SA. Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat. Br J Pharmacol 2012; 166:1002–1017.
80. Hsu DC, Ananworanich J. Immune interventions to eliminate the HIV reservoir. Curr Top Microbiol Immunol 2018; 417:181–210.
81. Chun TW, Murray D, Justement JS, Blazkova J, Hallahan CW, Fankuchen O, et al. Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. Proc Natl Acad Sci U S A 2014; 111:13151–13156.
82. Lu CL, Murakowski DK, Bournazos S, Schoofs T, Sarkar D, Halper-Stromberg A, et al. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 2016; 352:1001–1004.
83. Koppensteiner H, Banning C, Schneider C, Hohenberg H, Schindler M. Macrophage internal HIV-1 is protected from neutralizing antibodies. J Virol 2012; 86:2826–2836.
84. Sattentau QJ, Stevenson M. Macrophages HIV-1: an unhealthy constellation. Cell Host Microbe 2016; 19:304–310.
85. Duncan CJ, Williams JP, Schiffner T, Gartner K, Ochsenbauer C, Kappes J, et al. High-multiplicity HIV-1 infection and neutralizing antibody evasion mediated by the macrophage-T cell virological synapse. J Virol 2014; 88:2025–2034.
86. Hellmuth J, Colby D, Kroon E, Sacdalan C, Chan P, Intasan J, et al. Neurologic stability with brief analytic treatment interruption after early ART. In: CROI, 2018.
87. Crowell T, Colby D, Pinyakorn S, Intasan J, Benjapornpong K, Tanjnareel K, et al. The broadly-neutralizing HIV-specific monoclonal antibody VRC01 minimally impacts time to viral rebound during analytic treatment interruption in virologically-suppressed, HIV-infected participants who initiated antiretroviral therapy during acute HIV infection. In: IAS; 2017.
88. Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol 1994; 153:517–528.
89. Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9:301–309.
90. Farstad IN, Halstensen TS, Kvale D, Fausa O, Brandtzaeg P. Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes. Am J Pathol 1997; 150:187–199.
91. Byrareddy SN, Arthos J, Cicala C, Villinger F, Ortiz KT, Little D, et al. Sustained virologic control in SIV+ macaques after antiretroviral and alpha4beta7 antibody therapy. Science 2016; 354:197–202.
92. Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, Bennett CL. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009; 10:816–824.
93. Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol 2015; 8:130.
94. Viardot A, Bargou R. Bispecific antibodies in haematological malignancies. Cancer Treat Rev 2018; 65:87–95.
95. Gay CL, Bosch RJ, Ritz J, Hataye JM, Aga E, Tressler RL, et al. AIDS Clinical Trials 5326 Study TeamClinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy. J Infect Dis 2017; 215:1725–1733.
96. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014; 21:371–381.
97. Torino F, Corsello SM, Salvatori R. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol 2016; 28:278–287.
98. Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol 2017; 74:1216–1222.
99. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014; 15:e257–267.
100. Reardon DA, Mitchell DA. The development of dendritic cell vaccine-based immunotherapies for glioblastoma. Semin Immunopathol 2017; 39:225–239.
101. Garcia F, Climent N, Guardo AC, Gil C, Leon A, Autran B, et al. DCV2/MANON07-ORVACS Study GroupA dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci Transl Med 2013; 5:166ra162.
102. van der Sluis RM, van Montfort T, Pollakis G, Sanders RW, Speijer D, Berkhout B, Jeeninga RE. Dendritic cell-induced activation of latent HIV-1 provirus in actively proliferating primary T lymphocytes. PLoS Pathog 2013; 9:e1003259.
103. Norton TD, Miller EA, Bhardwaj N, Landau NR. Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro. Gene Ther 2015; 22:227–236.
104. Macatangay BJ, Riddler SA, Wheeler ND, Spindler J, Lawani M, Hong F, et al. Therapeutic vaccination with dendritic cells loaded with autologous HIV type 1-infected apoptotic cells. J Infect Dis 2016; 213:1400–1409.
105. Mothe B, Moltó J, Manzardo C, Coll J, Puertas M, Martinez-Picado J, et al. Viral control induced by hivconsv vaccines & romidepsin in early treated individuals. In: CROI; 2017.
106. Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 2012; 4:132ra153.
107. Deeks SG, Wagner B, Anton PA, Mitsuyasu RT, Scadden DT, Huang C, et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther 2002; 5:788–797.
108. Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 2000; 96:785–793.
109. Hale M, Mesojednik T, Romano Ibarra GS, Sahni J, Bernard A, Sommer K, et al. Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells. Mol Ther 2017; 25:570–579.
110. Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood 2017; 130:2295–2306.
111. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016; 127:3321–3330.
112. Borducchi EN, Cabral C, Stephenson KE, Liu J, Abbink P, Ng’ang’a D, et al. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature 2016; 540:284–287.
113. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr, Buckley N, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 2015; 522:487–491.
114. Chan P, Colby D, Valcour V, Sailasuta N, Krebs S, Jagodzinski L, et al. CNS monitoring of cART interruption in individuals treated during Fiebig I acute HIV. In: CROI, 2017.
115. Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med 2014; 161:319–327.
116. Gray F, Lescure FX, Adle-Biassette H, Polivka M, Gallien S, Pialoux G, et al. Encephalitis with infiltration by CD8+ lymphocytes in HIV patients receiving combination antiretroviral treatment. Brain Pathol 2013; 23:525–533.
117. Crowell TA, Hatano H. Clinical outcomes and antiretroviral therapy in ’elite’ controllers: a review of the literature. J Virus Erad 2015; 1:72–77.
118. Crowell TA, Gebo KA, Blankson JN, Korthuis PT, Yehia BR, Rutstein RM, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis 2015; 211:1692–1702.
119. Cunningham C, Hennessy E. Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimers Res Ther 2015; 7:33.
120. Yilmaz A, Blennow K, Hagberg L, Nilsson S, Price RW, Schouten J, et al. Neurofilament light chain protein as a marker of neuronal injury: review of its use in HIV-1 infection and reference values for HIV-negative controls. Expert Rev Mol Diagn 2017; 17:761–770.
121. Strain JF, Burdo TH, Song SK, Sun P, El-Ghazzawy O, Nelson B, et al. Diffusion basis spectral imaging detects ongoing brain inflammation in virologically well controlled HIV+ patients. J Acquir Immune Defic Syndr 2017; 76:423–430.
122. Wang Y, Wang Q, Haldar JP, Yeh FC, Xie M, Sun P, et al. Quantification of increased cellularity during inflammatory demyelination. Brain 2011; 134 (Pt 12):3590–3601.
123. Santangelo PJ, Rogers KA, Zurla C, Blanchard EL, Gumber S, Strait K, et al. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat Methods 2015; 12:427–432.
124. Boerwinkle A, Ances BM. Molecular imaging of neuroinflammation in HIV. J Neuroimmune Pharmacol 2019; 14:9–15.
125. Tawakol A, Ishai A, Li D, Takx RA, Hur S, Kaiser Y, et al. Association of arterial and lymph node inflammation with distinct inflammatory pathways in human immunodeficiency virus infection. JAMA Cardiol 2017; 2:163–171.
126. Vaidyanathan S, Patel CN, Scarsbrook AF, Chowdhury FU. FDG PET/CT in infection and inflammation--current and emerging clinical applications. Clin Radiol 2015; 70:787–800.
127. El Fakhri G, Trott CM, Sitek A, Bonab A, Alpert NM. Dual-tracer PET using generalized factor analysis of dynamic sequences. Mol Imaging Biol 2013; 15:666–674.
128. Price RW, Paxinos EE, Grant RM, Drews B, Nilsson A, Hoh R, et al. Cerebrospinal fluid response to structured treatment interruption after virological failure. AIDS 2001; 15:1251–1259.
129. Price RW, Deeks SG. Antiretroviral drug treatment interruption in human immunodeficiency virus-infected adults: Clinical and pathogenetic implications for the central nervous system. J Neurovirol 2004; 10: (Suppl 1): 44–51.
130. Gisslen M, Rosengren L, Hagberg L, Deeks SG, Price RW. Cerebrospinal fluid signs of neuronal damage after antiretroviral treatment interruption in HIV-1 infection. AIDS Res Ther 2005; 2:6.
    131. Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest DJ. A5170 Study TeamNeurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010; 74:1260–1266.

    antiretroviral interruption; central nervous system compartmentalization; central nervous system latency; HIV cure

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