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HIV and the Brain: Report from the
15th Conference on Retroviruses and Opportunistic Infections.
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Scott Letendre1 , J. Allen McCutchan1, and Ronald J. Ellis2
Departments of 1Medicine and 2Neurosciences,
University of California, San Diego
Antiretroviral Treatment of the Central Nervous System
Overview
The effectiveness of antiretrovirals in the nervous system (or neuroeffectiveness) has been debated since the observation that zidovudine may more consistently benefit people with AIDS dementia than didanosine [1, 2]. Even though potent combination antiretroviral therapy (ART) has led to declines in the incidence of many complications of HIV infection [3-5], the prevalence of central nervous system (CNS) disease has remained stable or increased, suggesting that its treatment may be suboptimal [6, 7]. Numerous studies have assessed whether the extent of ART penetration into the CNS is a determinant of neuroeffectiveness [8-26]. These studies used varying estimates of neuroeffectiveness and diverse outcome measures, making direct comparisons difficult. For example, to assess penetration, some studies focused on individual drugs, others used an additive penetration "score", and others directly measured antiretroviral concentrations in CSF. Clinical outcome measures in these studies were also diverse, ranging from clinical staging to neuropsychological (NP) testing to neuroimaging methods such as magnetic resonance spectroscopy. Up until recently, these varying methods yielded inconsistent results which have failed to resolve the controversy about the clinical importance of CNS penetration.
Because findings in the past were inconsistent, new strategies have been devised to improve the accuracy of neuroeffectiveness estimates. Accurate estimates of neuroeffectiveness should be particularly useful for the estimated 30-50% of people living with HIV who have neurologic complications, such as HIV-associated neurocognitive disorders (HAND) [27], Progressive Multifocal Leukoencephalopathy (PML), or Cryptococcal meningitis. The CHARTER (CNS HIV AntiRetroviral Therapy Effects Research) Group recently published an analysis based on an approach to estimating neuroeffectiveness that accounts for all available data on molecular and pharmacologic characteristics, pharmacokinetics, and clinical effectiveness [28].
In brief, one study at this year's conference demonstrated that ART that had estimates of better neuroeffectiveness was associated with better global NP performance (Abstract 391). A second analysis identified that, among individuals who had HIV-associated neurocognitive disorder (HAND) prior to initiating ART, estimates of better neuroeffectiveness were associated with better recovery (Abstract 68). An autopsy study linked estimates of better ART neuroeffectiveness, particularly for non-nucleoside reverse transcriptase inhibitors (NNRTIs), to a lower prevalence of HIV-associated brain pathology at death (Abstract 67) and a fourth study linked estimates of better ART neuroeffectiveness to better survival following a diagnosis of PML (Abstract 385). Data on tenofovir concentrations in cerebral spinal fluid (CSF) were also shown, confirming low concentrations that averaged only 5% of those in blood (Abstract 131).
Based on these and other findings, what recommendations can be made for people living with HIV and their care providers? First, antiretroviral neuroeffectiveness should be discussed by treaters and patients when selecting ART regimens. Admittedly, ART regimen selection is already complex, requiring consideration of multiple issues, such as dosing simplicity, risk of side effects, and drug resistance. Despite this, neuroprotection may be more important to some patients than dosing simplicity, for example, and so they should be given the option to consider this when making treatment decisions. Second, people living with HIV should be regularly screened for the symptoms of HAND [29, 30], which include difficulty remembering, reading, and learning new information, and can lead to problems with taking medications, employment, and other important activities. If screening indicates problems, then additional testing should be performed [27]. Third, if a person living with HIV does have evidence of HAND and is not yet on ART, then they should strongly consider starting a neuroeffective ART regimen. This might be true even if they already have drug resistance in blood since ART can sometimes still be effective in the CNS even when it is not in blood [31]. When this situation occurs, a neuroeffective NNRTI, like nevirapine, may provide particular benefit. Fourth, since ART alone may not normalize cognitive impairment in a substantial minority of individuals, consider adjunctive therapies. While no adjunctive therapies have yet been proven consistently effective, memantine may provide some benefits [32]. Further, a clinical trial of minocycline for HAND is currently enrolling in the AIDS Clinical Trials Group (http://www.aactg.org/). While the findings supporting these recommendations remain mostly observational, they are increasingly consistent and the neuroAIDS community is working to provide even more supportive data in the coming years.
Discussion
At this year's conference, investigators from the National Institute of Infectious Disease (Rome) group further validated the CNS penetration-effectiveness (CPE) ranking approach by comparing it to another system that they had used in prior, published analyses. In this observational study of 185 HIV-infected volunteers, NP test batteries were administered before ART initiation and at follow-up (Abstract 391). Similar to other recent cohort studies, half (50%) of the subjects had impaired NP performance at baseline. Higher CPE ranks (denoting greater neuroeffectiveness) correlated with greater improvements in NP performance. In contrast, higher estimates of neuroeffectiveness with the alternative ranking approach did not. These findings were confirmed by another longitudinal study (Abstract 68). In this analysis of volunteers with HAND, Letendre and colleagues also identified that higher CPE ranks were associated with greater improvements in NP performance. Prospective application of the CHARTER ranking system to the treatment of people with HAND is now being tested in an ongoing, NIH-funded, randomized clinical trial based in Baltimore, St. Louis, and San Diego ([33]; www.clinicaltrials.gov).
The importance of ART neuroeffectiveness was highlighted by two other studies. The National NeuroAIDS Tissue Consortium (NNTC), which is based in Galveston/Houston, Los Angeles, New York City, and San Diego, presented data from 374 volunteers who died from AIDS-related complications (Abstract 67). NNTC neuropathologists examined brain tissue obtained at autopsy, identifying that 76 (20%) had two common forms of HIV-associated brain pathology (HBP), HIV leukoencephalopathy [34] or HIV encephalitis [35-37]. Those who had HBP had more advanced immunosuppression (lower current and nadir CD4+ cell counts in blood) and higher HIV RNA levels in blood prior to death and, consistent with these findings, were less likely to report ART use. This analysis used a variation of the CPE ranking approach, summing the CPE ranks for all antiretrovirals reported during the antemortem observation period rather than for a single regimen. Estimates of greater cumulative neuroeffectiveness (i.e., higher CPE ranks) were associated with a lower likelihood of HBP at autopsy (P = 0.03). A potentially important additional finding was that volunteers who reported use of a non-nucleoside reverse transcriptase inhibitor (NNRTI) during the antemortem observation period had a substantially lower likelihood of HBP at autopsy (NNRTI-containing regimen 12% vs. PI-containing regimen without an NNRTI 22% vs. no ART 28%, P = 0.03). The neuroeffectiveness of NNRTIs, like nevirapine, is supported by this analysis of nearly 400 people but the current analysis does not distinguish whether the observed associations might be attributable to other factors linked to NNRTI use.
Using data from the FHDH cohort (French Hospital Database on HIV), Gasnault and colleagues showed that the benefits of neuroeffective ART may not be limited to the neurologic complications of HIV alone but may also improve survival in those who have CNS opportunistic diseases (Abstract 385). In a retrospective analysis of over 1,400 individuals, they found that survival after a PML diagnosis improved dramatically in the combination ART era as compared to earlier treatment periods. Only 20% of individuals who were diagnosed with PML between 1992 and 1995 survived one year. In comparison, 54% of individuals survived one year for the other three treatment periods (1996-1998, 1999-2002, 2003-2004). Survival was worst among those who did not take ART. Among those who did take ART, regimens with better estimated neuroeffectiveness (CPE ranks of at least 1.5) had a 6-fold lower risk of death even after adjusting for other potentially influential demographic factors, such as age, AIDS diagnosis prior to PML diagnosis, nadir blood CD4+ cell count, gender, and HIV transmission risk factor. These results suggest that control of HIV replication in the CNS plays a role in recovery from PML. A limitation of this study was its failure to account for the number and potency of antiretroviral agents in patients regimens which would provide some assurance that the effects were due to potency in the CNS specifically, rather than simply overall systemic efficacy or immune recovery. For instance, Gasnault also demonstrated a survival benefit (77% at 6 months) in an interim analysis of 26 individuals who enrolled in a trial of intensified ART (tenofovir-emtricitabine-efavirenz-lopinavir-ritonavir-enfuvirtide) for PML that was reported at last year's conference (Abstract 379). While the study regimen selected for this trial includes drugs that are more (lopinavir-ritonavir, emtricitabine) and less (tenofovir, efavirenz, enfuvirtide) neuroeffective, survival was linked to recovery of JC Virus-specific immune responses, emphasizing that recovery from PML probably requires both viral and host factors.
The accuracy of the CPE ranking system should improve as more CSF pharmacology data are generated. The estimated neuroeffectiveness of tenofovir, for example, is rated as suboptimal, but, up until now, this estimate was based on inferences from drug characteristics, such as poor fat solubility, anionic charge, and the activity of organic anion transporters. More direct data supporting the limited neuroeffectiveness of tenofovir in the nervous system were presented by Best and colleagues (Abstract 131). Tenofovir concentrations were measured in body fluids from 187 volunteers of the CHARTER (CNS HIV AntiRetroviral Therapy Effects Research) study, identifying that the concentrations in cerebral spinal fluid (CSF) were low (median 5.5 ng/mL, interquartile range 2.7-11.3) and averaged only 5% of the concentrations in blood plasma. Compare these concentrations to the higher concentrations of two nucleoside analogues, abacavir (median concentration in CSF 128 ng/mL, mean CSF-to-plasma ratio 36% [38]) and lamivudine (median concentration in CSF 470 nM, mean CSF-to-plasma ratio 15% [39]). In the tenofovir analysis, two-thirds of CSF specimens had concentrations below 7 ng/mL and 30% of these specimens had HIV RNA levels in CSF above 50 copies/mL. In the one-third of CSF specimens that had tenofovir concentrations above 7 ng/mL, only 5% had HIV RNA levels above 50 copies/mL (P = 0.02 for the comparison between the 2 groups). Together, these data support that the neuroeffectiveness of tenofovir is limited and may be inferior to abacavir or lamivudine (from Jules: or perhaps FTC), although a direct comparison is needed to confidently reach this conclusion.
A contrasting viewpoint to the idea that some antiretrovirals are neuroprotective is that some may directly or indirectly injure the brain. Data from Husstedt and colleagues support direct injury by some antiretrovirals, namely dideoxynucleoside analogues (DDNs: didanosine, stavudine, and zalcitabine) (Abstract 389). The toxic effects of these drugs on the brain have long been suspected based on their link to peripheral neuropathy (e.g., [40]) and to a neuromuscular weakness syndrome (stavudine, [41]). In a retrospective, cross-sectional analysis, 60 individuals who were taking ART that included DDNs (mean duration 19 months) were compared to controls who were taking ART without DDNs. Use of DDNs was associated with a higher prevalence of impaired NP performance (P < 0.009). These findings need to be confirmed in longitudinal and interventional studies but, if confirmed, would add to the existing evidence of the adverse consequences of DDNs, which continue to be commonly used in resource-limited settings.
Favoring indirect injury of the brain by ART, Letendre and colleagues presented data supporting that an intended consequence of effective ART, immune recovery, might injure the brain under certain circumstances, such as when individuals have pre-existing HAND (Abstract 68). In this analysis, 25 individuals with HAND initiated a new ART regimen and were followed for 24 weeks. Nearly all subjects (88%) improved their NP performance by 24 weeks but the extent of improvement varied widely between individuals (change in the Global Deficit Score, median -0.53, interquartile range (-0.79) - (-0.19)). Only 15 (60%) normalized their NP performance by 24 weeks. Those who improved the least (or not at all) had lower nadir blood CD4+ cell counts and higher HIV RNA levels in CSF, both prior to treatment, and greater expansions of blood CD8+ cell counts during treatment (linear regression model R2 = 0.48, P = 0.0001]). This combination of lower CD4+ cell counts before treatment, higher antigen levels within the CNS, and greater expansion of CD8+ cells, which can home to and injure the nervous system [42], suggest that recovery from HAND may be limited by an neuroimmune process directed at HIV antigens that is similar to the Immune Reconstitution Inflammatory Syndrome (IRIS, e.g., [43, 44]). Thus, ART might be a double-edged sword which can either benefit or injure the brain depending on clinical conditions.
One other ART-associated condition that may affect the brain is antiretroviral resistance. Prior analyses have demonstrated that some antiretroviral resistance mutations can result in reduced replication capacity in lymphocytes and may be associated with lower viral loads and virulence [45-47]. The idea that some drug resistant mutants may also have reduced replication capacity in brain cells, such as microglia, was supported by data presented by Hightower et al (Abstract 394). In this study of 94 volunteers, drug resistance mutations were detectable in 48 (51%) with the most common resistance mutations being M184V/I (20%) and K103N (15%). Drug resistance, particularly M184V/I, was associated with lower HIV RNA levels in CSF (2.6 vs. 3.3 log10 copies/mL, P = 0.009) - but not in blood - and better NP performance, particularly among those who had definite normal or definite impaired performance (P = 0.05). This analysis also identified that higher HIV RNA levels were associated with worse NP performance but only among those who did not have drug resistance, providing a possible explanation for the weakening of this relationship in the combination ART era (e.g., [24]).
Susceptibility to HAND
Overview
HAND is thought to be attributable to a combination of viral, host, and comorbid factors. For instance, Gabuzda and colleagues have identified that highly neurotropic HIV isolates (i.e., isolates having an affinity for or adapted to the cells of the nervous system [48]) can be isolated from brain tissue from individuals dying with HAND and that these isolates replicate with reduced dependence on CD4 [49] and enhanced macrophage tropism [50] (In the brain, macrophages and microglia are the primary target cells for HIV). Others have identified that host factors, such as variability in the chemokine, CCL2, are strongly associated with the risk of HAND [51, 52]. Comorbidities are a third important determinant of risk and include disparate conditions such as infection with other pathogens (e.g,. Hepatitis C Virus (HCV) [53-55], use of recreational stimulants (e.g., methamphetamine [56], and advancing age [57, 58].
Investigators at this year's conference presented important new information in each of these 3 major categories.
Σ Regarding the effects of the virus on the brain, Gray and colleagues identified that dual/mixed HIV isolates (i.e., mixtures of isolates that can use either of the primary HIV chemokine receptors, CCR5 or CXCR4) still seem to primarily use CCR5 in the brain. This might be important because it suggests that CCR5 inhibitors could protect the brain even when they are no longer effective in the blood and lymph tissue. Sacktor and colleagues presented data supporting the conclusion that subtype D, which is common in Uganda where the study was performed, may more readily injure the nervous system than subtype A, which is also common in Uganda, or subtype B, which predominates in the U.S. and Europe. Identifying the basis for these differences in brain injury between the subtypes of HIV may lead to new treatments for HAND (Abstract 404b).
Σ Regarding host effects, several studies focused on the importance of the immune system in controlling HIV in the nervous system. Perhaps the most important identified a genetic variant in the major histocompatibility complex (MHC) that seemed to protect macaques from brain injury from simian immunodeficiency virus (SIV). If this is confirmed in human studies, it could lead to development of a genetic screening test for HAND (Abstract 72).
Σ Regarding comorbidities, one study identified that a bacterial product, lipopolysaccharide (LPS), may increase the risk for HAND when it is found in blood. LPS can be present in the blood of people with HIV because the virus injures lymphoid tissue in the intestinal wall, increasing its permeability and allowing bacteria that normally live within the gut to more easily enter the body. This is important because LPS activates the immune system and can lead to greater HIV replication and immune deterioration [59]. At the conference, Ancuta and colleagues identified that higher levels of LPS were associated with a nearly 4-fold increased odds of having HIV-associated dementia (Abstract 69).
These important observations and others at the conference will lead to additional research but, unfortunately, none have been sufficiently validated to enable their use in the clinic as tests that will either diagnose or predict future risk for HAND. For now, patients and care providers should continue to rely on clinical diagnosis, as described in the recent updated diagnostic nosology [27].
DISCUSSION
Susceptibility to NeuroAIDS - Viral Correlates
HIV primarily enters its target cells in the brain via the chemokine receptor, CCR5 [60]. Consistent with this, several studies have identified that brain-derived HIV isolates from people dying with AIDS are more likely to use CCR5 [61] and be macrophage-tropic even when isolates from tissues outside the nervous system, such as the spleen, used CXCR4 and replicated in T-cell lines [62]. Dual-mixed HIV strains have only been infrequently isolated from brain tissue but Gray and colleagues characterized isolates from two individuals (one with HAND, one with CNS lymphoma) to better understand how they influence HIV nervous system disease (Abstract 397). Even though the envelope proteins derived from brain were dual-mixed, they more easily bound to CCR5 and fused with the cell membrane (i.e., they were more fusogenic), important early steps in the entry of HIV into target cells. In contrast, matched dual-mixed envelope proteins from spleen or blood more easily fused with cell membranes that expressed another chemokine receptor, CXCR4. The investigators identified that all clones from brain tissue of the individual dying with HAND had a particular deletion (they were missing an asparagine residue at position 11 in the V3 loop (R306S) that was present in spleen clones). Additional experiments confirmed the importance of this mutation in determining coreceptor usage in the brain isolates. Together, these findings support that dual-mixed HIV isolates still predominantly use CCR5 in the brain, which has implications for the neuroeffectiveness of CCR5 inhibitors, like maraviroc and vicriviroc, even when dual-mixed HIV is present in blood.
The importance of the HIV envelope in HAND was supported by work from Pillai and colleagues from the CHARTER Group (Abstract 401). To validate their prior finding that a serine at position 5 of the V3 loop of HIV-1 gp160 (N300S) was associated with HAND [63, 64], the investigators sought this mutation in matched CSF and blood plasma specimens from 39 volunteers, 19 of whom had HAND. As hypothesized, the N300S mutation was more common in volunteers who had HAND (P < 0.03). While the positive predictive value of this mutation for the presence of HAND was high (86%), the sensitivity was low (33.3%). Thus, the investigators confirmed their prior finding in an independent cohort but the poor sensitivity in this analysis argues against the clinical utility of this mutation for identifying presence or risk of HAND.
In addition to env, other HIV genes, such as tat, have been implicated in neuropathogenesis. Most of the investigations supporting the role of HIV genes derive from the U.S. and Europe, where clade B HIV infections predominate, but non-clade-B infections are more common in the rest of the world. The genetic differences between HIV clades may influence neuropathogenicity [65]. Three studies at this year's conference assessed the potential influence of viral diversity on HIV neurologic complications.
Sacktor et al studied HIV-infected individuals in Uganda, where HIV clades A, C, and D are common (Abstract 404b). Sixty ART-naive, HIV+ individuals from Kampala who had blood CD4+ cell counts below 200 cells/ƒÊL were evaluated. Subtype assignments were generated by sequence analysis based on portions of gag and gp41. Evaluations included a neurological examination, an 8-test neuropsychological test battery, and assessments of daily function. A higher proportion of subjects infected with subtype D met study criteria for dementia (8/9, 89%), compared to only 24% (7/33) of those infected with subtype A. This difference was not explained by group differences in age, education, gender, blood CD4+ cell counts, or HIV RNA levels in blood. The mechanism by which subtype D may confer greater neurovirulence is yet to be determined. A strength of this study was that all patients were from the same geographic region, reducing the impact of factors other than subtype that could lead to observed differences in HIV-associated neurologic disease.
Robertson et al reported the baseline findings of a multisite, international study performed in Brazil, India, Malawi, Peru, South Africa, Thailand and Zimbabwe (Abstract 388), the most widely representative assessment of neurocognitive complications of HIV in international settings to date. Prior to ART initiation, subjects underwent a structured neurological examination and a brief neuropsychological (NP) assessment that focused on motor performance. In contrast with studies using more comprehensive NP assessments, these screening tests revealed a low prevalence of HIV dementia (2 cases, 0.2%) and minor neurocognitive disorder (19 cases, 2.2%) among the 860 enrolled patients. By contrast, 87 subjects (10%) had evidence of peripheral neuropathy. While there was significant variation in neurocognitive test performance across countries, many factors might explain these differences, including host genetics, cultural customs, opportunistic infections, co-infections, substance use, populations, cultures, HIV subtypes, or variation in test administration.
In a third international study, Valcour and colleagues performed two analyses of data from Thai volunteers infected with the A-E circulating recombinant form (CRF) of HIV (Abstract 387). First, in a cross-sectional analysis of data from the SEARCH 005 study, a cohort with undetectable HIV RNA levels in blood that were nested in the 2NN clinical trial [66], they identified that 36% (8/22) had mildly impaired global NP performance. Second, in a prospective, treatment trial (SEARCH 001), ART was administered to 30 volunteers, half of whom had HAND. Even though HIV RNA levels were reduced below detection, those who had HAND continued to perform worse at 6 and 12 months, confirming the limited effectiveness of combination ART in individuals infected with A-E CRF.
Susceptibility to NeuroAIDS - Host Correlates
Genetic variants that influence that affect CNS disease in humans are well known, particularly in neuroimmunology. For example, multiple sclerosis (MS) is associated with certain susceptible major histocompatibility complex (MHC) haplotypes. The MHC is present in many species and the human form is termed the human leukocyte antigen (HLA) system. This group of genes resides on chromosome 6 and encodes cell-surface antigen-presenting proteins and other genes. The major HLA antigens are essential elements in immune function and are broadly categorized as either class I or class II. Class I antigens (A, B, and C) present peptides from inside the cell (including viral peptides) and class II antigens (DR, DP, and DQ) present phagocytosed antigens from outside of the cell to T-cells. Prior analyses have identified that MHC class II expression was elevated in the brains of individuals dying with HIV encephalitis [67] and was restricted to macrophages/microglia, the primary target cells of HIV in the brain.
In this context, Mankowski et al reported an HLA haplotype that may specifically affect CNS retroviral disease (Abstract 72). They studied an accelerated simian immunodeficiency virus (SIV) encephalitis model in pigtailed macaques. This animal model is characterized by a shortened asymptomatic interval and an increased incidence of CNS disease compared to other SIV models. In 60 macaques, an MHC allele, Mane-A*10, seemed to protect animals from SIVE (24% vs. 67%, odds ratio 6.0, P = 0.003) but was unrelated to SIV RNA levels or CD4+ cell counts in blood, suggesting that protection from CNS disease was not related to slower immune disease progression but rather to a CNS-specific action of the allele. This was supported when lower levels of SIV RNA levels, activated (CD68+) macrophages, and amyloid precursor proteins were identified in the brains of macaques that had the protective Mane-A*10 allele, compared to control animals.
Migration of lymphocytes and macrophages is an important component of the host response to HIV in the nervous system and can lead to persistent immune-mediated injury despite apparent control of HIV in blood by ART. Even though CD8+ T-cells, such as effector memory and cytotoxic T-cells, play important roles in control of HIV in the brain and other organs, they can also cause injury to host tissues, particularly in the context of ART-induced immune recovery. Two studies provided supportive evidence of the importance of CD8+ T-cells in the nervous system by surface-phenotyping cells from CSF. Sadagopal and colleagues assessed the frequency of HIV-specific CD8+ T-cells in 7 volunteers who had very low levels of HIV replication in blood and very slowly progressive HIV disease ("immune controllers"). The frequencies of HIV-specific CD8+ T-cells in CSF averaged 2.4-fold greater than in blood (P = 0.0004). The enrichment of HIV-specific CD8+ T-cells in CSF relative to blood in these individuals who had little HIV RNA in CSF and no neurocognitive symptoms argues that these cells are important for control of HIV in the CNS. However, these findings also reinforce concerns that the expansion of CD8+ T-cells following initiation of ART may lead to a robust immune response to HIV antigens in the brain with resulting injury.
In a second study, Spudich and colleagues compared activation markers of blood and CSF T-cells obtained from individuals who were recently infected with HIV to those who were chronically infected. The investigators identified high levels of CD8+ T-cell activation in cells from CSF but the relationship with HIV RNA levels varied by disease stage. Consistent with the idea that CD8+ T-cells help control HIV in the CNS, volunteers who had early HIV infection and high levels of activated CD8+ T-cells in CSF had low levels of HIV RNA in CSF. In contrast, volunteers who had chronic HIV infection and high levels of activated CD8+ T-cells in CSF had high levels of HIV RNA in CSF, suggesting that the T-cells were homing to the CNS in response to HIV antigens but were ineffective in controlling replication. Together, the findings from these two studies suggest that CD8+ T-cells help control HIV replication in the nervous system in early disease but, when HIV disease advances to later stages, the frequency and activation of these cells increase in the nervous system, possibly tipping the scales in favor of injury rather than control.
Susceptibility to NeuroAIDS - Comorbidities
Recent findings indicate that the majority of all CD4+ T lymphocytes are lost during acute HIV infection, with mucosal compartments being most severely affected. The frequency of infection is very high in gut CD4+ T-cells and is associated with increased gut permeability and microbial translocation, which is evident as circulating lipopolysaccharide (LPS) [59]. Higher LPS levels in blood correlate with CD8+ T-cell activation [68] and so may help drive HIV disease progression. Since LPS can also damage the blood-brain barrier and increase monocyte trafficking into the nervous system, Ancuta and colleagues studied its effect in 119 HIV+ volunteers, 82 of whom had neurocognitive impairment (Abstract 69). They found that levels of LPS were higher in blood of subjects who had HIV-associated dementia (> 79 pg/mL: odds ratio 3.8, P = 0.007) but not milder forms of HAND and that this association remained significant even after adjusting for CD4+ cell counts and HIV RNA levels in blood. Thus, immune activation stemming from HIV-mediated injury of the gut and microbial translocation may be an important determinant of risk for progression to both AIDS and neuroAIDS.
Ancuta and colleagues also identified that LPS levels in blood were higher in individuals who were co-infected with HCV, supporting that this may be another mechanism by which this common comorbidity may injure the brain. Two studies argue that this may be increasingly important. Letendre and colleagues presented data from 401 volunteers in Anhui, China in collaboration with Peking University and the National Center for AIDS/STD Control and Prevention in China. In this cohort of former plasma donors, the prevalence of HCV seropositivity was high (46% if HIV+, 26% if HIV-) even though none of the volunteers used intravenous drugs. Among all subjects, those who had impaired neuropsychological performance were much more likely to be HCV co-infected (50% vs. 31%, P < 0.001). Among those who were HIV+, HCV and AIDS were independently associated with HAND (50% of those having both conditions had HAND). Thus, in China, HCV may be an even more important comorbidity predisposing HIV+ individuals to brain injury than it is in the U.S. and Europe.
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