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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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
apolipoprotein E; China; cognitive impairment; HIV; host genetics; mannose-binding lectin-2