APOE ϵ4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors
Spector, Stephen Aa; Singh, Kumud Ka; Gupta, Saurabhb; Cysique, Lucette Ad; Jin, Huab; Letendre, Scottc; Schrier, Rachelc; Wu, Zunyoue; Hong, Kun Xe; Yu, Xinf; Shi, Chuanf; Heaton, Robert Kb; the HNRC Group
aDepartment of Pediatrics, USA
bDepartment of Psychiatry, USA
cDepartment of Medicine, University of California San Diego, La Jolla, California, USA
dUniversity of New South Wales, Sydney, Australia
eNational Center for AIDS/STD Control and Prevention, China
fBeijing Mental Health Institute, Peking University, Beijing, China.
Received 29 December, 2009
Revised 22 February, 2010
Accepted 8 March, 2010
Correspondence to Stephen A. Spector, MD, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0672, USA. Tel: +1 858 534 7055; fax: +1 858 534 7411; e-mail: firstname.lastname@example.org
Background: Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese individuals infected through contaminated blood products.
Methods: Two hundred and one HIV-infected patients from Anhui, China, had neuropsychological tests at baseline and 12 months. DNA was genotyped for APOE ϵ2, ϵ3 and ϵ4 alleles; MBL2-A/O; CCR5-wt/Δ32; CCR5-59029-G/A; CCR2-180-G/A; SDF-1-G/A; IL4-589-C/T; MCP-1-2518-A/G; CX3CR1-745-G/A; −849-C/T polymorphisms and CCL3L1 copy number variants using real-time PCR. Univariate and multivariate analyses were performed.
Results: The cohort included 61% men, with mean education 5.5 years, AIDS diagnosis 113 (55%), on antiretrovirals 114 (56%), mean baseline CD4+ cell count 349 cells/μl and mean log10 RNA 4.09. At baseline, 37% had global neuropsychological impairment increasing to 44% after 12 months. Of 43 patients with the APOE ϵ4 allele, 58% were cognitively impaired compared with 31% without the ϵ4 allele (P = 0.001, odds ratio 3.09, 95% confidence interval 1.54–6.18). The mean global deficit score (GDS) for ϵ4-positive participants on antiretrovirals for 12 months was 0.88 (0.55) compared with 0.63 (0.54) for ϵ4-negative participants (P = 0.053, 95% confidence interval −0.004 to 0.51). For MBL2, 52% of patients with the O/O genotype declined in cognitive function over 12 months compared with 23% with A/A (odds ratio 3.62, 95% confidence interval 1.46–9.03, P = 0.004). No associations were observed for the other genetic variants.
Conclusion: The APOE ϵ4 allele was associated with increased risk for cognitive deficits, whereas the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese individuals infected with HIV through contaminated blood products.
Recent estimates are that 33 million people are living with HIV-1 infection worldwide . Although estimates of HIV-1 infection in China have been difficult to establish, approximately 700 000 people were living with HIV-1 infection in China in 2007 with an estimated prevalence of 0.05%. An estimated 85 000 Chinese have AIDS with 35 000 of those infected through blood donation and transfusion. In 2007, there were an estimated 50 000 new infections and 20 000 deaths.
The initial recognition of HIV-1 infection in China was among injection drug users (IDUs) in the city of Ruili located in Yunnan's Dehong prefecture [2,3]. Unregulated commercial blood/plasma collection with re-used needles among farmers between 1992 and 1995 in several provinces in central China, including Henan, Anhui and Shanzi, resulted in rapid spread of infection among blood donors and recipients of blood products. In many cases, blood products were also contaminated with hepatitis C virus (HCV), resulting in transmission of both viruses. These early transmissions led to an increased risk for HIV-1 transmission among gay men and heterosexual contacts. Estimates are that of the 1.3 billion people living in mainland China, 30–50 million are at high risk for infection, including IDUs and their sexual partners, sex workers their clients and their partners and men who have sex with men.
The central nervous system (CNS) is an important target of HIV-1 and a common cause of neurological impairment. With the increased use of combination antiretroviral therapy (ART), severe dementia is less common; however, milder forms of HIV-associated neurocognitive disorders (HANDs) remain an important complication of HIV-1 infection, affecting 30–50% of person living with HIV-1 [4–8]. Until recently, no study has systematically evaluated the neurobehavioral effects of HIV-1 among people in China. Recently, our group  reported the results of the initial comprehensive evaluation of 201 HIV-infected former plasma donors in Anhui Province. Using a global summary score, neuropsychological impairment was found in 37% of persons infected with HIV-1 and 13% of an uninfected control group. As expected, persons with AIDS were more likely to be impaired than those HIV-infected who had less advanced disease. Of interest, persons with neuropsychological impairment were more likely to report cognitive complaints and increased dependence in daily functioning. In a 12-month follow-up assessment, 27% of individuals in the original HIV-infected cohort developed significant cognitive decline that was predicted at baseline by AIDS status, lower nadir CD4+ cell count and lower performance in processing speed . These findings indicate that HAND is an important clinical syndrome in China and emphasize the importance of developing measures to treat and prevent HIV-related CNS disease.
An abundance of data from persons living in the United States and other Western countries indicates that virus–host interactions play a central role in HIV-1 pathogenesis, and host genetic factors are important determinants for risk of infection and disease progression. Host genetic variants are also associated with the presence and development of HANDs in adults and children [11–15]. From the emerging data, it is clear that no single genetic variant is the causal risk factor for HANDs, and multiple genes affecting innate and adaptive immunity, and neuronal susceptibility can alter the risk for impairment. No data exist for the evaluation of host genetic factors that affect HIV-associated neuropsychological impairment in Chinese. For this reason, our original study was designed to assess the association of host genetic variants that have been linked to HIV-related disease progression, cognitive impairment or both in United States and European cohorts. Our findings suggest that variants in genes encoding apolipoprotein E (apoE) and mannose-binding lectin-2 (MBL2) are associated with neuropsychological disorders in Chinese infected predominantly through contact with contaminated blood products.
Participants and methods
Details of the individuals who participated in this study have been described previously . The study was approved by the Institutional Review Boards from the China Center for Disease Control/National Center for AIDS, the Peking University, and the University of California, San Diego. Written informed consent was obtained from the participants after the research procedure had been fully explained to them. HIV-1 infection was confirmed by the HIV Quick Test (OraSure Technologies, Bethlehem, Pennsylvania, USA). Participants shared the infection risk of being a former plasma donor and only one participant in the HIV-1-infected group reported homosexual contact as an additional risk for HIV-1 transmission. Individuals with comorbidities that might cause neurocognitive impairment (other than coinfection with HCV) were excluded from the study. Briefly, of 203 HIV-1-infected individuals enrolled in the study, 201 had blood spots obtained for extraction of DNA for genetic studies, the basis for the analyses in this manuscript. HCV serostatus was determined using routine clinical HCV antibody testing. Of note, 93% of the HIV-infected cohort and 62% of the HIV-uninfected controls were HCV positive. Although there was not an increased rate of neurobehavioral impairment in the HIV/HCV coinfected majority versus the small HIV monoinfected group (36.9 versus 35.7%, respectively), a modest HCV effect was seen among the HCV-positive/HIV-negative compared with the HCV-negative/HIV-negative persons (23.5 versus 12.5%, respectively).
Demographic and medical history information was obtained from each participant. Each participant underwent comprehensive neurocognitive and neuromedical evaluations, a structured psychiatric examination and an assessment of daily functioning . Details of the neuropsychological battery selection and adaptation for use in China have been described previously by our group [9,16]. Briefly, the tests used for neurobehavioral function were decided jointly by US and Chinese investigators who evaluated the entire HIV Neurobehavioral Research Center (HNRC) neurobehavioral protocol to gauge each test's appropriateness for use in China. The battery was carefully reviewed by Chinese mental health professionals, who considered the US tests to be culturally appropriate with only minor modifications for the study populations in China. The tests were translated by the Chinese investigators from English to Mandarin. Back-translation was performed independently by a professional translator with no prior knowledge of these instruments. The test battery used evaluates multiple cognitive–motor ability domains that repeatedly have been found to be affected by HIV-associated brain disease in the United States [17–19]. All test scores in the battery were adjusted for age, education and sex using data from demographically comparable HIV-seronegative former plasma donors from the same rural Chinese region .
Genomic DNA extraction and genotyping
Genomic DNA extracted from dried blood spots using QIAamp DNA Mini Kit (Qiagen, Valencia, California, USA) was genotyped for CCR5-wt/Δ32, CCR5-59029-G/A, CCR2-180-G/A, SDF-1-G/A, IL4-589-C/T, MCP-1-2518-A/G, MBL2, APOE 2060-T/C and 2198-C/T (distinguishing ϵ2, ϵ3 and ϵ4 alleles), CCL3L2 copy number variants (CNVs) and CX3CR1-745-G/A, −849-C/T polymorphisms using real-time PCR (LightCycler; Roche, Basel, Switzerland) as described previously [13,20,21]. These genetic variants were selected because each has previously been found to be associated with HIV-related disease progression, neurocognitive impairment or both.
For bivariate analyses, categorical variables were compared using either the χ2 test or the Fisher's exact test. Continuous variables were compared using the Student's t-test for parametric data or the Mann–Whitney U-test for nonparametric data. All genetic variant comparisons analyzed were based on differences between genotypes or haplotypes previously identified in other cohorts to be associated with HIV-1-related disease. Two-tailed P values were considered significant if less than 0.05.
Demographic data and genotype frequencies
Table 1 shows the demographic, laboratory and cognitive function data of the HIV-infected individuals at baseline (N = 201) and at 12 months of follow-up (N = 192). The cohort was comprised of 60.7% men with a mean education of 5.5 years. AIDS was diagnosed in 113 individuals at baseline and 114 were receiving ART. The mean CD4+ lymphocyte count at baseline was 349 cells/μl, which increased to 400 cells/μl at 12 months. The plasma HIV-1 RNA was detectable in 127 individuals at baseline with the mean viral load of 4.09 log10 copies/ml. At baseline, 74 (37%) individuals were globally impaired, which increased to 85 (44.2%) after 12 months of follow-up. Table 2 gives the frequencies for each of the genes assessed. Of note, no individuals were found to have the CCR5Δ32 allele.
Association of APOE ϵ4 genotype with HIV-related cognitive impairment
Individuals with the ϵ4 allele had less education than those without the ϵ4 allele (mean 4.6 versus 5.7 years, respectively); however, all global deficit score (GDS) assessment were adjusted for age, sex and education. Because the ϵ4/ϵ4 genotype was present in only two (1%) individuals, all analyses that examined the association of ϵ4 were performed using the presence or absence of the ϵ4 allele. Presence of the ϵ4 allele was more likely to be associated with cognitive impairment (adjusted for age, sex and education). Of the 43 individuals with the ϵ4 allele, 25 (58%) were cognitively impaired compared with 49 (31%) of 158 without the ϵ4 allele [P = 0.001, odds ratio (OR) 3.09, 95% confidence interval (CI) 1.54–6.18) (Table 3). The increased likelihood of impairment held whether individuals were on ART at baseline (P = 0.042, OR = 2.64, 95% CI 1.04–6.68) or not (P = 0.018, OR = 3.75, 95%CI 1.28–11.0). The mean GDS (±SD) at baseline was 0.61 (0.51) for individuals with the ϵ4 allele and 0.46 (0.47) for those without ϵ4 (P = 0.015).
Because high viral load and low CD4+ lymphocyte counts have been associated with HANDs, we examined the CD4+ cell counts and viral loads of individuals with and without the ϵ4 allele. Of note, individuals with the ϵ4 allele had higher baseline CD4+ lymphocyte counts (414.9 ± 229.0 versus 331.6 ± 179.3, respectively, P = 0.016) and their mean nadir CD4+ cell count did not differ from those without the ϵ4 allele (274.1 versus 246.5, respectively, P = 0.31). The proportion of individuals with an AIDS diagnosis and HIV viral load did not significantly differ between the two groups. The associations between APOE ϵ4 genotypes at baseline held in multivariate analyses controlling for CD4+ lymphocyte count, HIV viral load or both (P < 0.01 for all comparisons).
We next assessed the association of the ϵ4 allele on cognitive impairment at 12 months of follow-up. For the 192 HIV-infected individuals with neurocognitive evaluations at 12 months, those with the ϵ4 allele were no more likely to be impaired than those without ϵ4 (48 versus 43%, respectively, P = 0.73). Notably, individuals with the ϵ4 allele were no more likely to be on ART at baseline or during the 12 months of follow-up compared with those without the ϵ4 allele. However, whereas the 23 ϵ4-positive participants on treatment during the 12 months had a mean (±SD) GDS score of 0.88 (0.55), the mean GDS for the ϵ4 negatives was 0.63 (0.54) (P = 0.053, 95% CI −0.004 to 0.51). This association held in multivariate analyses controlling for baseline CD4+ lymphocyte count (P = 0.036), but failed to reach statistical significance controlling for viral load (P = 0.08) or CD4+ cell count and viral load (P = 0.067). Similar findings were observed when controlling for 12-month CD4 cell count, viral load or both (P = 0.031, 0.073 and 0.054, respectively).
Because genetic variants in APOE have been found to have a profound effect on the development of Alzheimer's disease and other neurodegenerative disease, we examined the impact of age on the association of ϵ4 variants with cognitive impairment at baseline. For these analyses, we compared individuals between 20 and 39 years of age (n = 22) with those at least 50 years old (n = 8). For the 20–39-year-old group of those positive for the ϵ4 variant, 13 (59%) were impaired at baseline compared with five (63%) in the at least 50-year-old group (OR = 0.87, 95% CI 0.16–4.58, P = 1.00). Whereas being ϵ4 positive was associated with cognitive impairment in the 20–39-year-old group (n = 78, OR = 0.31, 95% CI 0.12–0.82, P = 0.02), the association was not present in the at least 50-year-old individuals (n = 24, OR = 0.6, 95% CI 0.11–3.4, P = 0.68).
Association of MBL2 genotypes with HIV-related cognitive impairment
At baseline, no significant differences in rates of cognitive impairment were observed for study participants with different MBL2 genotypes (Table 3). For the A/A group, 40 of 104 (38.5%) were impaired compared with 26 of 72 (36.1%) of the A/O group and eight of 25 (32%) for the O/O group (P = 0.64 for A/A versus O/O). By the end of 12 months of follow-up, 41, 43 and 60% of participants were impaired in the A/A, A/O and O/O groups, respectively. There was a trend toward increased impairment in the O/O group compared with the A/A group (OR 2.13, 95% CI 0.8829–5.28, P = 0.09). Of note, whereas 13 (52%) of participants with the O/O genotype experienced a decline in cognitive function over the 12-month period, only 23 (23%) of participants in the A/A group demonstrated declining cognition (OR 3.6, 95% CI 1.46–9.03, P = 0.004). This association held in multivariate analyses controlling for CD4+ lymphocyte count, viral load or both at baseline (P < 0.006 for each).
Genetic variants CCR2-180G/A (V/I), CCR5-59029-G/A, IL4-589C/T, MCP1-2518-A/G and CCL3L1 copy number variation fail to show any association with global neuropsychological impairment
Genetic variants in genes encoding for MCP-1 (CCL2) and its receptor CCR2, CCL3L1 CNV and receptor CCR5 and IL-4 have each been associated with HIV disease progression, cognitive impairment or both in some HIV-infected cohorts generally from the United States or Western Europe. Table 2 summarizes the allelic and haplotype frequencies of each of the additional genetic variants evaluated. In our HIV-infected Chinese cohort, no association was observed with any of these genetic variants with the global deficit score at baseline or after 12 months of follow-up (Table 4).
An increasing body of data supports an important role for host genetics in the pathogenesis of HIV-1 disease. Most studies, to date, have been performed in cohorts from countries where there is little representation of persons of Chinese origin and none have examined genetic associations on HANDs in persons living in China. Thus, our findings indicating that genetic variants in APOE and MBL2 are associated with cognitive impairment in HIV-infected Chinese who acquired their infection through exposure to contaminated plasma are novel, and are consistent with the important roles that apoE and MBL2 are thought to play in the pathogenesis of HIV infection.
ApoE has a central role in lipid metabolism, and genetic variants have been implicated in the development and progression of cardiovascular, neurological and infectious diseases . ApoE has a particularly important role in the plasma clearance of trigyceride and cholesterol-rich lipoproteins and is the major ligand for the low-density lipoprotein (LDL) receptor. It is also the ligand for other members of the LDL receptor family including the LDL-receptor-related protein, which contributes to lipoprotein remnant clearance. ApoE binds to heparin sulfate proteoglycans, which also clear apoE-containing remnant lipoproteins (for review see [23,24]). The finding of an association of APOE genetic variants with an impaired GDS is of particular interest. ApoE is an important carrier of cholesterol in the CNS and has been identified as a risk factor in Alzheimer's disease (for review see ). Detrimental effects of the apoE4 isoforms correlate with the structure of apoE (for review see ). ApoE has two structural domains separated by a hinge region; the N-terminal domain contains the receptor-binding region, whereas the C-terminal domain contains the major lipid-binding region. Amino acid variations in these regions have been shown to have dramatic effects on apoE structure. Persons heterozygous or homozygous for APOE ϵ4 are at increased risk for Alzheimer's disease compared with those with other apoE isoforms. The presence of the ϵ4 allele also decreases the age at which persons are at risk for development signs of Alzheimer's disease. Additionally, it appears that there is a synergistic negative effect between the ϵ4 allele and amyloid-β on the risk for Alzheimer's disease .
Corder et al.  were the first to examine the association of APOE genetic variants and HIV-related dementia. In their small predominantly white cohort, the presence of the ϵ4 allele was associated with twice the risk for HIV-related dementia as well as an excess risk for peripheral neuropathy. Also, in a study by Valcour et al.  the presence of APOE ϵ4 was associated with increased risk for HIV-associated dementia in older patients but not in younger patients. More recently, Burt et al.  found that ϵ4 homozygosity in a US cohort was associated with more rapid HIV-related disease progression and death when compared with those homozygous for ϵ3. However, no association was observed with the presence of the ϵ4 allele and HIV-associated dementia. In the current study, the ϵ4 allele was found to be present in a greater proportion of cognitively impaired HIV-infected Chinese than those with the other apoE isoforms. Moreover, for those receiving antiretroviral treatment over the 12-month period, the ϵ4 allele remained associated with cognitive impairment. The association of ϵ4 with impairment was unaffected by age in our study; however, because only eight participants were at least 50 years old, we cannot definitively exclude that the association with the APOE ϵ4 with HIV-related cognitive impairment does not increase with age.
How apoE variants are associated with an increased risk for infectious diseases is an area of active investigation. However, apoE isoforms have been associated with susceptibility to a broad spectrum of microorganisms including malaria, bacterial infections and viral infections including herpes simplex and HIV-1 . Additionally, in-vitro studies demonstrate that in the presence of apoE4 cells are more susceptible to HIV-1 infection than cells treated with apoE3 . The susceptibility of cells to HIV-1 infection appears to be mediated by the amphiphatic helices of apoE interacting with the HIV gp41 protein promoting viral fusion. The structure of apo4 leading to a decreased capacity to block the binding of gp41 to the cell or the differential effects on the cholesterol content or other lipids on the target cell may be responsible for the enhanced replication. Thus, it is possible that the apoE4 isoform both enhances HIV-1 infection and provides an increased susceptibility to cognitive impairment. Of interest, the apoE4 isoform is more frequent in African populations in which its role in the HIV/AIDS epidemic has not been examined.
MBL2 is an evolutionarily conserved, circulating host protein encoded by the MBL2 gene. It is an important component of the innate immune system and binds to the mannose residues present on some bacteria, parasites, yeast and viruses, mediating complement activation, opsonization and phagocytosis [30–32]. MBL2 exon 1 variants result in single amino acid changes affecting oligomerization of MBL. Homozygous wild-type (A/A) sera contain predominantly fully functional MBL, whereas homozygous mutant sera (O/O = any combination of B, C or D alleles) contain mostly low-molecular-weight MBL. Sera containing heterozygous variant alleles (A/O, O = B, C or D) contain both high-molecular-weight and low-molecular-weight MBL, with the ratio determined by the promoter type on the normal haplotype (A allele). Low-molecular-weight MBL2 can result in opsonic defects, and has been linked to an increased risk for several inherited immunodeficiencies, autoimmune diseases and risk for serious infectious diseases, including acute respiratory infections and meningococcal disease [31,33,34]. Additionally, MBL2 genetic variants have been associated with HIV-related disease progression in both adults and children [35,36]. Of note, Singh et al.  have identified an increased risk for progression to CNS impairment in HIV-1-infected children in the United States with the O/O genotype compared with those with either the A/O or A/A genotypes. Little is known of the effect of MBL2 variants in the Chinese population or the association of MBL with HIV-related cognitive impairment. Thus, the findings presented here of an increased risk for development of cognitive impairment in a cohort of HIV-infected Chinese adults over the course of 12 months are novel, but are consistent with previous association studies performed in the United States.
The current study has a number of limitations. First, the timing of HIV-1 infection was not established so that participants could have been infected at any time when they were exposed to contaminated blood drawing equipment. Second, there was not documentation of when ART was initiated for those on treatment. However, there was consistency of the drugs used for treatment with first-line therapy in China with most study participants receiving two nucleoside reverse transcriptase inhibitors and nevirapine. Third, because such a large proportion of the participants were HCV seropositive, it is possible that the effects seen may reflect an additive contribution to impaired cognitive performance and is not representative of HIV-1 infection alone. Finally, because the participants in this study were infected through blood products, these findings may not be applicable to persons infected with HIV-1 through sexual transmission. In total, however, our findings do suggest that the APOE ϵ4 allele and MBL2 O/O genotypes are associated with neurobehavioral outcomes in HIV-infected Chinese. These findings will need to be confirmed in additional cohort studies in China to define further the associations between these genetic variants and HIV-related CNS impairment.
This study was supported by the National Institute of Mental Health (NIMH) grant #5RO1MH073433, the HNRC grant #MH 62512 and NIMH grant #5R01MH085608. We thank Rodney Trout and Patricia Riggs for their technical assistance and help with data collection, respectively.
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