In addition to infection of circulating and tissue CD4+ T lymphocytes that results in immunodeficiency and systemic immune activation, HIV-1 also can infect nonlymphoid cells and organs [1–3]. These extralymphoid cellular targets importantly include myeloid and other cells within the central nervous system (CNS) [4,5]. The recent focus on HIV-1 eradication or remission has increased attention to nonlymphoid reservoirs for HIV-1 that may require unique intervention, with the CNS as a key consideration given unique biological properties of this compartment and challenges in its assessment.
Studies of the brain and cerebrospinal fluid (CSF) in people living with HIV-1 (PLWH) have consistently shown abnormalities in biomarkers of inflammation and injury along with neurocognitive dysfunction, consistent with early and perhaps ongoing CNS perturbation despite effective systemic antiretroviral therapy (ART) [6–8]. Furthermore, ‘compartmentalized’ viral replication can persist or emerge within the CNS during ART (most commonly detected as ‘CSF HIV-1 escape’, where HIV-1 RNA is measured in the CSF at a higher level than in the plasma) [9–11]. As the overwhelming majority of PLWH start ART after many years of infection, virtually all studies identifying these signs of CNS perturbation during have focused on individuals who initiated ART in chronic infection, presumably after long-established disease. However, more recent understanding of CNS HIV-1 pathogenesis along with observations of the impact of early treatment on systemic HIV-1 reservoirs has provoked the question of whether intervention with ART early during the course of HIV-1 infection may reduce the establishment or persistence of HIV-1 infection in the CNS compartment.
Precedence for early benefit of antiretroviral therapy in the central nervous system: early antiretroviral therapy to reduce systemic HIV-1 reservoirs
Increased posttreatment viral control after early antiretroviral therapy
Seminal work indicating that latent HIV-1 in resting CD4+ T lymphocytes is virtually impossible to eradicate even after almost a lifetime of effective ART demonstrated the importance of HIV-1 reservoirs as a barrier to cure . However, the case reported 10 years ago of the ‘Berlin patient’ who demonstrated no plasma HIV-1 rebound after stem cell transplantation from a donor homozygous for CCR5 delta32 galvanized the field to an aspirational goal of viral cure . Although numerous therapeutic approaches to this goal have been promulgated, one of the most promising were observations in the Visconti cohort where individuals who initiated ART during early infection than interrupted ART was associated with rates of posttreatment (and interruption) HIV-1 control higher than expected rates in the general HIV-infected population [14,15]. These observations have been confirmed to varying extents in other early treatment cohorts that demonstrate reduced viral reservoir measurements or delayed or reduced viral rebound after ART interruption compared with later ART [16–18]. Although initial reports were clinical observational studies that did not include extensive biological measures, the interpretation of these studies was that early ART may enhance posttreatment control in part by limiting establishment of HIV reservoirs, leading to lower viral setpoints or lack of viral rebound after ART interruption.
Further studies have subsequently been reported indicating benefits of early treatment on HIV-1 pathogenesis as well as examining the possibility that early ART may reduce HIV-1 reservoirs. Reduced levels of blood CD4+ and CD8+ T-cell activation and lower cell associated HIV-1 DNA and RNA measures in PBMC were observed in those starting ART within 6 months after initial infection compared with after 2 years duration of HIV-1 . A key case of an infant with perinatal HIV-1 infection – reported in the lay press as the ‘Mississippi baby’ – treated with a full antiretroviral regimen at 30 h of age was identified as having no detected HIV-1 RNA in the plasma and exceedingly low levels of HIV-1 DNA detected in PBMC 12 months after discontinuation of ART .
Early antiretroviral therapy in acute HIV reduces biomarkers of the systemic HIV-1 reservoir
The effect of intervention with ART during very early acute HIV-1 has been extensively examined in the RV254/SEARCH 010 cohort study conducted in Bangkok, Thailand. Identifying individuals with positive HIV-1 nucleic acid testing through screening at a large anonymous sexually transmitted infection testing center, this study has to date enrolled over 600 antibody-negative acute HIV-1 participants at a median of 19 days after estimated infection . Individuals are further defined by Fiebig stage (see Table 1) . More than 95% of individuals choose to start immediate ART within 2 days of enrollment. Quantitative measures of HIV-1 DNA in PBMC after 6 months of ART were lower in these participants than in historical comparison with participants who had started ART during chronic infection . In some participants starting ART in Fiebig I, HIV-1 DNA was not detectable in PBMC. A recent study in the USA confirmed these findings in two individuals who were identified after they had started antiretrovirals for preexposure prophylaxis (PrEP) during early Fiebig I . This study additionally did not detect HIV-1 RNA or DNA in other tissues including gut, lymph node and CSF, and demonstrated lack of HIV-1 outgrowth in assays that serve as functional tests of the ability of CD4+ T lymphocytes to induce replication of HIV-1 in target cells in one of these two early treated individuals.
Early antiretroviral therapy alone does not lead to systemic HIV-1 remission
Although findings of posttreatment controllers, delayed rebound, and low levels of HIV-1 DNA after early ART raised optimism that early ART may be a strategy to reduce viral reservoirs enough to enhance chances for sustained HIV-1 remission, these hopes have been largely disappointed by recent studies. Among these include the observation that 27 months after cessation of ART started soon after birth, the Mississippi child had a viral rebound in the plasma accompanied by a drop in her CD4+ T-cell count, indicating that the tiny levels of HIV-1 DNA in the blood or levels elsewhere in unmeasured tissues were enough to eventually overcome posttreatment control . In the RV254/SEARCH 010 cohort, abnormal elevations of key soluble plasma immune biomarkers despite sustained ART started within weeks of HIV-1 infection suggested a variety of possible causes including perturbations because of HIV-1 persistence . Finally, in a systematic study of ART interruption in a small group of individuals who started ART during Feibig I infection in RV254/SEARCH 010, HIV-1 rebounded in all participants with only a slight delay beyond that reported after treatment in chronic infection . Corollary findings were reported in one of the two individuals identified during PrEP in San Francisco who experienced plasma viral rebound after a sustained ART-free remission of over 7 months .
These and other findings indicate that though HIV-1 reservoirs may be substantially limited by early ART, reducing quantifiable HIV-1 measures and delaying viral rebound after ART cessation, early ART alone will not suffice in achieving ART-free systemic HIV-1 remission. Despite these largely negative clinical findings, it remains plausible that CNS HIV-1 infection may differentially benefit from early ART because of unique dynamics of HIV-1 entry and establishment of local immune activation and compartmentalization in the CNS compartment.
Dynamics of central nervous system infection and neuropathogenesis in early HIV
Clinical neurological manifestations of HIV-1 seroconversion illness, including meningitis, encephalopathy, myelopathy, acute mononeuropathy, and polyradiculopathy have been reported since early in the epidemic, suggesting very early viral or immune disorder in the nervous system in some individuals [28–34]. HIV-1 RNA in the CSF and brain tissue have also been detected during the initial weeks after initial infection in both asymptomatic and neurosymptomatic individuals [35–38]. Although brain tissue is difficult to sample directly in humans, systematic studies including sampling of the CSF and neuroimaging measures have further delineated the emergence of viral replication, immune activation, and injury in the CNS during early infection. A schematic of these processes over the first 6 months of HIV infection is shown in Fig. 1.
Detection of HIV RNA in cerebrospinal fluid in untreated early HIV preantiretroviral therapy
Ninety-six participants with ‘primary HIV-1 infection’ (defined as within 12 months of laboratory-confirmed infection) were studied in collective early HIV-1 cohorts in San Francisco, USA (the Primary Infection Stage CNS Events Study, or PISCES), Gothenburg, Sweden, Milan, Italy and Sydney, Australia. At a median of 77 days after estimated infection, 85% of participants had quantifiable CSF HIV-1 RNA, with median values of 3.07 log10 copies/ml, approximately 1.5 log10 lower than that in concurrently sampled plasma . In the RV254/SEARCH 010 study of acute HIV, CSF HIV-1 was first detected as early as 8 days after infection, in Fiebig I infection , and at median 18 days after infection, HIV-1 RNA was measurable (>80 copies/ml) in 77%, with the highest levels of HIV-1 RNA in CSF reached in Fiebig stage 4 (n = 117) . The differential between plasma and CSF HIV-1 RNA was greater in this very early acute stage than later in the course of infection, at 2.36 log10 copies/ml, although the median level in CSF was higher (3.76 log10 copies/ml) because of the high peak plasma viremia in acute infection; one participant had a CSF HIV-1 RNA level of over 4 million copies/ml at estimated 30 days postinfection.
Immune activation and inflammation in the central nervous system in early HIV preantiretroviral therapy
Influx of immune cells into the CNS, initiation of local immune responses, and disruption of the blood–brain barrier are key to the initiation and control of HIV-1 infection within the CNS, as well as viral neuropathogenesis. Activated CD4+ and CD8+ lymphocytes as well as monocytes cross the blood–brain and blood–CSF barriers, initiating CNS immune activation; infected immune cells also transmigrate to the CNS, leading to local viral replication. In CSF, the lymphocyte chemokine CXCL-10, monocyte chemokine CCL-2, and the macrophage activation pteridine biomarker neopterin rise in early acute infection, as early as Fiebig I infection [40,42,43]. At a median 3 months into untreated infection, CSF CXCL-10 and neopterin are elevated even in individuals with levels of HIV-1 RNA lower than the limit of detection of the standard assay . CSF neopterin progressively rises over the ensuing months until treatment is initiated, suggesting increasing macrophage/microglial activation . Cellular immune activation is initiated early in CSF, with expansion of activated CD8+ lymphocytes in the CSF in acute infection by Fiebig III, detection of HIV-specific CD8+ lymphocytes in CSF, and, interestingly, enrichment of unique CD8+ T-lymphocyte clonotypes in the CSF versus the blood that indicate distinct cellular immune responses in the CNS compartment as early as the first weeks after infection . Total CSF white blood cell counts (WBCs) are mildly elevated at 3 months after infection .
CSF protein and the CSF/blood albumin ratio are mildly elevated in the first months, indicating disruption of the blood–brain or blood–CSF barriers, which is characteristic of late stage infection and HIV-1 associated dementia, but not typically detected in asymptomatic chronic HIV-1 . Neuroimaging approaches detect inflammatory changes in multiple regions of the brain parenchyma almost immediately after initial HIV-1 infection. Brain magnetic resonance spectroscopy (MRS) in the RV254/SEARCH 010 acute HIV-1 cohort reveals elevations in inflammatory brain metabolite measures choline and myoinositol in early acute infection [40,47]. Inflammatory changes detected in the same brain regions in individuals first studied a few months into infection progressively increase over time in the absence of ART .
Biomarkers of neuronal injury in early HIV preantiretroviral therapy
Signs of injury to neurons are delayed compared with viral and immune/inflammatory changes in early infection, with no detectable rise in CSF neurofilament light chain (NFL) a biomarker of axonal damage in acute HIV-1 participants in the RV254/SEARCH 010 cohort, and no evidence for white matter tract damage on diffusion tensor imaging (DTI) [49,50]. However, in other cohorts, neuronal injury measures are abnormal in untreated individuals just a few months after HIV-1 acquisition, including elevations in CSF NFL in about half of individuals, reductions in N-acetylaspartate, a neuronal integrity MRS marker, and evident white matter changes on DTI [51–53]. Degree of neuronal injury in this early stage associates with elevations in myeloid immune activation or blood–brain barrier disruption. Reductions in volume of focal brain structures start within the first months of infection, and progressively increase over the first years of infection until the initiation of ART [54,55].
Establishment of central nervous system HIV-1 infection: cerebrospinal fluid viral compartmentalization in early infection
Viral detection in the CSF suggests the transit of infected cells or potentially free virions from the blood into the CNS (including the brain, meninges, and CSF), but does not provide evidence for local infection of cells within the CNS. Such viral presence in the CNS would be putatively cleared by reduction of systemic viral replication and reduction of cellular trafficking into the CNS. Comparison of sequences of HIV-1 RNA derived from CSF with those in the blood provides a measure of ‘compartmentalization’ that, if present, suggests that local CNS cells are producing HIV-1 under distinct selection pressures or within disparate cell types than those generating HIV-1 in the blood. Chronic HIV-1 and HIV-associated dementia are frequently characterized by extensive CSF viral compartmentalization, with some HIV-1 variants functionally adapted to replicate well in cells with low CD4+ receptor density. This suggests that local CNS cells – in some cases, myeloid lineage cells – are productively infected by HIV-1. The time course of establishment of compartmentalization in the progression of HIV-1 is important to determine the onset of local CNS replication, and thus, the possibility of HIV-1 persistence in the CNS once ART is initiated.
Studies employing single genome amplification (SGA) to examine subtype CRF01_AE envelope sequences between CSF and blood in 10 individuals in the RV254/SEARCH 010 acute HIV-1 cohort at a median 19 days postinfection showed no significant genetic compartmentalization . However, follow-up studies in this cohort using next generation sequencing to deeply sample populations including minor variants has demonstrated differential enrichment of variants in the CSF compared with the blood in individuals with multiple transmitted/founder viruses at acute infection . These findings may reflect that in some cases, either a genetic bottleneck in viral transmission to the CNS, or distinct selection pressures including compartmentalized immune responses in the CNS may set the stage for eventual emergence of unique compartmentalized CNS variants.
CSF compartmentalization of HIV-1 subtype C has been detected using SGA in children with perinatal HIV-1 as early as 5 months of age . In cases of mother-to-child transmission of multiple transmitted/founder viruses, early sequestration of one variant almost exclusively to the CNS was sometimes observed, consistent with the suggestion in adult acute infection that variants may become differentially established in the CNS early after transmission. Next generation sequencing of protease and reverse transcriptase in paired CSF and blood samples from five adults with early infection revealed compartmentalized linked resistance mutations in one individual at estimated 3.6 months postinfection .
In a larger survey, compartmentalization of env was detected within 4 months of estimated HIV-1 infection by SGA, with up to 20% of individuals harboring compartmentalized HIV-1 variants within the CNS by the second year of infection [60,61]. Most compartmentalized variants were T-cell tropic, though some demonstrated intermediate phenotypes of macrophage tropism, perhaps suggesting a step towards adaptation to infection of resident CNS target cells. Crucially, longitudinal assessment of samples derived from individuals who did not start ART revealed cases where compartmentalized populations diversified over time only in the CNS compartment, indicating persistent replication initiated as early as 4 months postinfection locally within cells of the CNS.
Is there evidence of a benefit of early antiretroviral therapy on central nervous system HIV-1 persistence?
There is no data that definitively indicate a benefit of early initiation of ART on persistence of HIV-1 within the CNS compartment. Direct measures of CNS HIV-1 persistence in living humans are elusive, and additionally, limited studies have traced CNS responses to early initiation of ART. A putative link between CNS inflammatory biomarkers and viral persistence in the CNS compartment is suggested by the fact that in lymph node and gut, viral persistence directly associates with level of local tissue immune activation [62,63]. Moreover, detection of low-level HIV-1 RNA in CSF has been shown to associate with elevations in the CSF macrophage activation marker neopterin among individuals treated during chronic HIV-1 [7,64]. Thus, several human studies have assessed CSF and neuroimaging to determine the effects of early ART on biomarkers of neuropathogenesis, such as neuroinflammation that may reflect viral persistence.
Benefit of early antiretroviral therapy on measures of intrathecal immune activation
When ART is started in acute infection in the RV254/SEARCH 010 cohort, abnormal elevations in CSF soluble immune activation biomarkers including CXCL-10, CCL2, neopterin and YKL-40 normalize after sustained months of ART, despite persistence of some elevated plasma immune biomarkers [42,43,65]. Similarly, preliminary studies indicated that initiation of ART in acute infection leads to a reduction in inflammatory brain metabolites as detected by MRS . However, identification of individuals in acute infection is highly challenging, and the question of whether initiation of ART in the early but not acute stage infection is similarly beneficial is clinically important.
In an unpublished study enrolling individuals within 1 year of infection in San Francisco, USA, we evaluated clinical CSF white blood cell counts and the macrophage activation marker neopterin in the blood and CSF before and after ART initiated approximately one and a half years of infection. Participants (n = 24) were sampled at a pre-ART baseline (median 4.6 months postinfection) and at an interval at least 6 months after starting ART initiated at variable times (median 17.7 months) after infection. CSF and blood data from primary HIV-1 infection participants were compared with that from 20 age-matched HIV-1-negative participants. At baseline pre-ART, CSF WBC, CSF neopterin, and plasma neopterin were significantly elevated compared with controls (all P < 0.05). After a median 8.1 months after ART initiation, median CSF measures were similar in primary infection participants and HIV-1 negative controls (Fig. 2); only blood neopterin remained significantly elevated compared with HIV-1 negatives (P = 0.03). Thus, after more than 6 months of ART initiated 1.5 years after infection, levels of CSF markers of inflammation and immune activation normalized, whereas plasma neopterin remained elevated compared with age-matched controls. These findings are in contrast to prior reports of persistent CNS immune activation in chronic infection, and may suggest a CNS-specific benefit of early initiation of ART outside of the acute HIV infection window.
However, in a larger study from this cohort, markers of blood–brain barrier integrity (CSF protein and CSF:blood albumin quotient) were elevated in the first months of infection and did not significantly change after 6 months of ART, suggesting that disruption of the blood–brain barrier may be slower to improve than intrathecal immune activation . Similarly, elevations of inflammatory neuroimaging biomarkers measured by brain MRS in this group stopped rising after ART but did not return to normal levels after 6 months of ART . Additional longitudinal follow-up is needed to assess whether blood–brain barrier measures, neuroimaging abnormalities, and CNS injury biomarkers differ from HIV-1 negative individuals in individuals treated within the first few years of infection, with the hope that treatment at this stage prevents or ameliorates many signs of chronic injury evident in those treated in chronic HIV-1.
Benefit of early antiretroviral therapy on measures of central nervous system HIV-1 RNA and HIV-specific antibodies
Neuroimmune activation is only a possible proxy for HIV-1 persistence or latency in the CNS. More direct measures of CNS viral persistence include detection of residual CSF HIV-1 RNA despite ART, and detection or quantitation of HIV-specific antiviral immune responses. In our experience, CSF HIV-1 RNA is rarely detected in individuals after sustained ART started during acute infection or within the first few years of infection if plasma HIV-1 RNA is suppressed ( and unpublished observation). Though long-term rates of asymptomatic CSF escape may be lower after early ART, the relationship between asymptomatic CSF escape and CNS HIV-1 persistence is uncertain.
Measurable HIV-specific immune responses may indicate the presence of viral antigen, and thus reflect viral reservoirs . In a recent study including individuals identified early during infection, anti-HIV-1 antibodies were detected in CSF and serum at similar levels in untreated participants at all stages, though antibodies emerged in CSF about 2 weeks later than in serum in the early course of infection . Levels of antibodies in these compartments were only slightly reduced in the setting of ART started in chronic HIV-1. Initiation of ART in primary infection was associated with a slight reduction in on-ART levels of HIV-specific antibodies in serum, but a far greater reduction in on-ART levels of HIV-specific antibodies in CSF (Fig. 3). These findings indicate a compartment-specific salutatory effect of early treatment in the CNS, possibly suggesting a lower burden of CNS HIV-1 persistence effected by early ART.
Signs of persistent HIV-1 in the central nervous system despite early antiretroviral therapy
Additional data suggest that early treatment may not ameliorate all signs of HIV-1 persistence. A recent study detected HIV-specific CD8+ T lymphocytes – which putatively serve as a marker of persistence of HIV-1 antigen – targeting all HIV-1 proteins in 8/12 individuals after 2 years of suppressive ART started during acute HIV-1 in the RV254/SEARCH 010 cohort . In the same study, HIV-1 DNA was detected in CSF cells in two of these participants during ART. Although is it unclear how these cellular measures related to the CNS reservoirs, it is possible that they reflect continued viral trafficking to the CNS or local HIV-1 persistence despite extremely early ART. Additionally, single genome sequencing of CSF and plasma envelope during suppressive ART has demonstrated sequences derived from CSF and plasma that did not cluster together in an individual who started ART within 3 months of infection . Next generation sequencing of this participant's pre-ART sample revealed compartmentalized antiretroviral drug resistance in CSF, raising the question of whether drug-resistant variants sequestered in the CNS during early infection associated with persistence of compartmentalized HIV-1 in the CNS once ART was initiated . An independent group phylogenetically examining HIV-1 DNA sequences from CSF cell pellets as compared with PBMC reported compartmentalization of proviruses in two out of three well-suppressed individuals treated during the first 4 months of infection .
Thus, although immune activation biomarkers and antibody levels demonstrate a benefit of early treatment that may be greater in the CNS than the periphery (see Fig. 4 for summary), cytotoxic T-cell and viral markers suggest possible persistence of HIV-1 despite early treatment. Additional studies are needed to better define these findings and to determine how early is early enough to durably impact CNS HIV-1 persistence.
Detection of CSF HIV-1 RNA and a rise in CSF cytokines associated with innate immune responses within days of initial infection are the initial hallmarks of a cascade of events in the nervous system during the earliest stages of human HIV-1 infection. Peak CSF HIV-1 RNA levels are reached soon after peak plasma HIV-1 RNA, coincident with first observations of adaptive immune responses in the CNS, and sequestration or enrichment of viral variants in CSF relative to blood. Over the ensuing months, compartmentalized unique viral variants can be detected in CSF, which evolve in the CNS independently in blood in the absence of ART, likely in response to unique compartment-specific immune pressures and cellular targets within the CNS. Although these dynamic processes are initiated early in the course of infection, many CNS immune and viral measures lag slightly behind those in the periphery, suggesting that the CNS compartment may sustain a lower early burden of injury or local infection than the lymph node or other sites of HIV-1 persistence in the body. Thus, it is possible that early initiation of ART that only partially reduces systemic HIV-1 reservoirs and minimally delays plasma viral rebound has a greater benefit in preventing or reducing CNS HIV-1 persistence.
One major limitation in determination of effects of early ART on persistence in the CNS is that the optimal measure of CNS HIV-1 persistence in living humans is currently unknown, as each of the biomarkers studied in CSF or blood are at best surrogates for direct measurement of latent reservoirs or sites of low-level replication deep within tissue of the brain or meninges. A recent report employing RNA scope to examine numerous tissues in simian immunodeficiency virus and simian human immunodeficiency virus-infected macaques demonstrated essentially equivalent levels of viral RNA in brain tissue in animals treated within 2 months of infection and untreated animals . If these findings can be extrapolated to the human host, additional early therapeutic interventions that reduce transmigration of HIV-infected immune cells or enhance immune control of CNS HIV-1 infection may be necessary to reduce or eliminate the long-term persistence of HIV-1 in the nervous system compartment.
We thank the volunteers who participated in the cited studies. The authors are currently supported by grants from the NIH including R01NS084911, R21MH118023, R01MH106466, R21MH118109, R01NS094067 and by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-717531). The original data presented in this manuscript was supported by NIH grants R01MH081772 and K23MH74466.
Conflicts of interest
There are no conflicts of interest.
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