TABLE 4.
Genetic Studies. List of studies performed using post-mortem brain tissues or blood-derived cells of HIV-infected and uninfected individuals. AAN, American Academy of Neurology, criteria for HAD diagnosis; AD, Alzheimer’s Disease; CN, cognitively normal; COMT, catechol O-methyl transferase; CSA, cognitive score for age; CSF, cerebrospinal fluid; DSM, Diagnostic and statistical manual of mental disorders; DTI, diffusion tensor imaging (neuroimaging); Frascati, Frascati criteria for HAND classification (CN; ANI, asymptomatic neurocognitive impairment; MND, mild cognitive disorder; HAD); GCS, global cognitive score; GDS, global deficit score; HIV−/Ctl, uninfected, healthy control; HAE, HIV-1-associated encephalopathy; HAND, HIV-associated neurocognitive disorders; HIVE, HIVE encephalitis; HAND, HIV associated neurocognitive disorders; NCI, Neurocognitive impairment; HAD, HIV-associated dementia; HIV+/CN, HIV+ cognitive normal subjects; LE, leukoencephalopathy; MCMD, minor cognitive and motor disorder; MDD, major depressive disorder; METH, methamphetamine; MRI, magnetic resonance imaging (neuroimaging); MSK, Memorial Sloan Kettering classification of HAD; NP, neuropsychological; NPI-O, neuropsychologically impaired but not definitely caused by HIV infection due to comorbid factor; PBMC, peripheral blood mononuclear cells; qRT-PCR, quantitative reverse transcription polymerase chain reaction, RFLP, restriction fragment length polymorphism; SNV, single-nucleotide variants; WES, whole-exome sequencing; WB, Western blotting; WGA, whole genome amplification.
| Study (References) | Groups included in the study (number of cases) | Area(s) of the brain or other tissue | Methods 1) NCI diagnosis 2) genetics | Gene, SNP, SNV, association (y = yes/n = no) |
|---|---|---|---|---|
| Dunlop et al. (1997) | HIV+ dementia (n = 32) or possible dementia (n = 24) vs. HIV+ no dementia (n = 73); dementia not defined as HAD; Paper mentions total n = 132 but data are shown for n = 129 | frontoparietal cortex, cerebral white matter, hippocampus, cerebellum, basal ganglia, brain stem, thoracic spinal cord | 1) HAD graded by physician: no dementia, possible dementia, dementia | ApoEε4 (n) for dementia and HIVE |
| 2) ApoE PCR and RFLP | ||||
| Corder et al. (1998) | HIV+ (n = 44) with (n = 11) or without dementia (n = 32) (neurological data for n = 43; dementia not defined as HAD) | Serum | 1) NP testing | ApoEε4 (y) |
| 2) ApoE Western blotting | ||||
| Sato-Matsumura et al. (1998) | HIV+ HIVE or LE (n = 44) vs. HIV+ no HIVE or LE (n = 30)) vs. HIV-/Ctl (n = 35) | Brain tissue and PBMC | 1) None, HIVE and/or LE | TNFα promotor (n), HLA-DR3 (n) |
| 2) PCR for SNPs | ||||
| Boven et al. (1999) | HIV+ HAD/ADC (n = 9) or HIV+ no HAD (n = 8) vs. HIV−/Ctl (n = 6) | Frontal cortex | 1) HAD/ADC: MSK | CCR5 ± Δ32 (y) |
| 2) RT-PCR for CCR5 ± Δ32 | ||||
| van Rij et al. (1999) | HIV+ HAD/ADC (n = 49) vs. HIV+ no HAD/ADC (n = 186) HIV−/Ctl (n = 5) | PBMC | 1) ADC (yes/no) 2) PCR and RFLP for CCR5 ± Δ32 and CCR2 ± 64I |
CCR5 ± Δ32 (y), CCR2 ± 64I (n) |
| Quasney et al. (2001) | HIV+ with HAD (n = 16) vs. HIV+ no HAD (n = 45) vs. HIV−/Ctl (n = 231) | Brain tissue and PBMC | 1) HAND/HAD: AAN, MSK | TNFα promotor (y) |
| 2) PCR for SNP TNFα promotor | ||||
| Gonzalez et al. (2002) | Adults: HIV+ with or without HAD (n = 1,151); Children: HIV+ with or without HAD (n = 592) vs. HIV−/Ctl (n = 270) | PBMC | 1) ADC (yes/no) 2) PCR for SNP, RFLP for CCL2 |
CCL2 (y) depending on genotype/SNP |
| Singh et al. (2003) | Children: HIV+ with or without neurological deterioration (n = 1,049) | PBMC | 1) Neurological and neurocognitive decline | CCR5wt/Δ32 (y), CCR5 SNPs (y), CCR2-64I (y), CXCL12 (y) |
| 2) PCR and RFLP for SNPs | ||||
| Cutler et al. (2004) | HIV+ HAD (n = 10) | Brain | 1) HAD/ADC: MSK | ApoEε4 (n) |
| 2) PCR for ApoE | ||||
| Diaz-Arrastia et al. (2004) | HIV+ with signs of HIVE (n = 270) | Brain | 1) None, HIVE | ApoEε4 (n), TNFα (n), IL-1B*2 (n), ILIRN*2 (n) |
| 2) PCR for SNP, RFLP for | ||||
| Singh et al. (2004) | HIV+/CN with follow-up testing for development of NCI (n = 121) | PBMC | 1) NP testing, GDS | CCR5-wt/Δ32 (n), CCR2-64I (y), CCL2/MCP1 (n) |
| 2) SNPs PCR and melting curve analysis for | ||||
| Valcour et al. (2004) | HIV+ HAD (n = 182) | Banked specimen | 1) HAD: AAN | ApoEε4 (y) for age ≥ 50 years |
| 2) PCR and RFLP for ApoE | ||||
| Shiramizu et al. (2006) | Children: HIV+ with HIVE (n = 27) | CSF | 1) HAE | CCL2/MCP1 SNP (y) |
| 2) PCR for SNP, RFLP | ||||
| Burt et al. (2008) | HIV+/CN with follow-up testing for development of NCI/HAD (n = 1,267) vs. HIV−/Ctl (n = 1,132) | Blood | 1) HAD (yes/no) | ApoEε4 (n) |
| 2) TaqMan PCR-based allelic discrimination | ||||
| Pomara et al. (2008) | HIV+ no HAD (n = 41) | Blood | 1) NP testing | ApoEε4 (y) |
| 2) PCR and RFLP for ApoE | ||||
| Pemberton et al. (2008) | HIV+ HAD/ADC (n = 56) For meta-analysis data from: Dunlop et al. (1997); Corder et al. (1998); Quasney et al. (2001), Diaz-Arrastia et al. (2004) | PBMC | 1) ADC (mild, moderate, severe, or vegetative) | ApoEε4 (n), IL-1α (n), IL-1β (n), IL-12 (n), TNFα (y) |
| 2) PCR and RFLP; and meta-analysis | ||||
| Levine et al. (2009) | HIV+ HAD/ADC (n = 26) vs. HIV+/CN (n = 117) | Brain tissue and PBMC | 1) HAD: AAN | CCL3 (y), CXCL12 (n), CCL2 (n), CCL5 (n) |
| 2) PCR and TaqMan PCR-based allelic discrimination assays for SNPs | IL-1α (n), IL-10 (n), TNFα (n) | |||
| Bousman et al. (2010) | HIV ± METH (n = 108) vs. HIV−/Ctl ± METH (n = 84) | PBMC | 1) Executive funct. deficit score | COMT (y) |
| 2) Multiplex PCR (SpectroCHIP) | ||||
| Joska et al. (2010) | HIV+ with different severity of HAND (n = 144), HIV−/Ctl (n = 50) | Blood | 1) HAND: Frascati | ApoEε4 (n) |
| 2) PCR and RFLP | ||||
| Spector et al. (2010) | HIV+ with and without HCV+ (n = 201) | Blood | 1) GDS | ApoEε4 (y), CCL2(n), CCL3L1(n), CCR5(n), CCR2(n), CXCL12(n), CX3CR1(n), IL-4(n), MBL2 (y) |
| 2) PCR and RFLP | ||||
| Sun et al. (2010) | HIV+ NCI (n = 17) vs. HIV+/CN (n = 27) vs. HIV−/Ctl/CN (n = 11) | PBMC | 1) NP impairment | ApoEε4 (n) |
| 2) PCR and RFLP | ||||
| Andres et al. (2011) | HIV+ with different severity of HAND/HAD/GCS (n = 48) vs. HIV−/Ctl (n = 39) | Blood | 1) GCS and HAD scale | ApoEε4 (y) |
| (HAD scale Power et al. (1995)) | 2) PCR for genotype | |||
| Chang et al. (2011) | HIV+ with different severity of HAND/HAD/GCS (n = 69) vs. HIV−/Ctl (n = 70) | Blood | 1) NP testing, domain- and global Z-scores | ApoEε4 (y) |
| 2) PCR for genotype | ||||
| Gupta et al. (2011) | HIV+ METH (n = 93) vs. HIV+ no METH (n = 84) vs. HIV- METH (n = 77) vs. HIV- no METH (n = 77), each with or without NCI | PBMC | 1) NCI, composite deficit score | DRD3 (y) for HIV+ METH group |
| 2) Multiplex PCR (SpectroCHIP) | ||||
| Singh et al. (2011) | Children: HIV+ with various degrees of CNS disease/NCI (n = 572) | PBMC | 1) Neurological and neurocognitive decline | HLA Class I alleles (y) HLA-Class II (y) |
| 2) Multiplex WGA (DNA), Luminex 100 platform | ||||
| Bol et al. (2012) | HIV+ HAD (n = 72) or HIV+ no HAD (n = 241); HAD criteria of DSM, AAN, Frascati | PBMC | 1) HAD: DSM, AAN, Frascati | Prep1 (y), CCR5-Δ32 (y), CCR2 (n), CCL2 (n), CCL3 (n), ApoE (n), DYRK1A (n), MOAP1 (n), PDE8A (n), SPOCK3 (n), TNFα (n), UBR7 (n) |
| 2) SNP analysis, chip and PCR methods | ||||
| Schrier et al. (2012) | HIV+ (n = 203) vs. HIV−/Ctl (n = 198); GDS for all | Whole blood | 1) HAND: GDS | HLA Class I alleles (y) HLA-DR*04 (y) ApoEε4 (y) |
| 2) Genotyping for HLA class I and II, ApoE | ||||
| Brown et al. (2012) | HIV+ HAD of various degrees based on MSK (n = 262) | Buccal swabs or PBMC | 1) HAD: MSK | CCL3L1 (n) |
| 2) qPCR for copy number | ||||
| Levine et al. (2012b) | HIV+ with MCMD or HAD (AAN) or ANI (Frascati) or no HAND/NCI (n = 184) | PBMC and/or other tissue | 1) NP testing and AAN | COMT (n), BDNF (n), DAT (n) |
| 2) Genotyping/SNPs | ||||
| Soontornniyomkij et al. (2012) | HIV+ with HAND/ANI (Frascati) or MCMD/HAD (AAN) (n = 160) vs. HIV−/Ctl (n = 22) | Brain tissue | 1) HAND/HAD: AAN, Frascati | ApoEε4 (y) |
| 2) ApoE genotype | ||||
| Morgan et al. (2013) | HIV+ with HAND (Frascati) (n = 466) | PBMC | 1) HAND: Frascati | ApoEε4 (n) |
| 2) ApoE genotype | ||||
| Panos et al. (2013) | HIV+ with MCMD or HAD (AAN) or ANI (Frascati) or no HAND/NCI (n = 259) | PBMC and/or other tissue | 1) HAND/HAD: AAN, Frascati | ApoEε4 (y) for age ≥ 50 years |
| 2) ApoE genotype | ||||
| Singh et al. (2013) | Children: HIV+ with various degrees of CNS disease/NCI (n = 1,049) | PBMC | 1) Neurological function | APOBEC3G (y), genotype dependent |
| 2) APOBEC3G genotype | ||||
| Hoare et al. (2013) | HIV+ with ApoEe4 ± vs. HIV+ no ApoEe4 (n = 24), neuropsych testing for all | PBMC | 1) NP testing | ApoEε4 (y) |
| 2) ApoE genotype | ||||
| Morales et al. (2013) | HIV+ with or without HAND/MCMD/HAD (AAN) (n = 20) vs. HIV−/Ctl (n = 16) | PBMC(?) and CSF | 1) HAND: AAN | YWHAE (y), genotype dependent |
| 2) Genotype/SNP for YWHAE (qPCR and WB) | ||||
| Levine et al. (2014) | HIV+ with or without NCI (n = 546) vs. HIV−/Ctl (n = 406) | PBMC | 1) HAND: Domain T-scores | CCL2 (y), CCL3 (y), CXCL12 (n), MBL (n) HIV+, (y) HIV-/Ctl, COMT (n) HIV+, (y) HIV-/Ctl |
| 2) Genotyping for SNPs | ||||
| Chang et al. (2014) | HIV+ with or without NCI (n = 80) vs. HIV−/Ctl (n = 97) | Whole blood | 1) HAND: NP testing or Frascati | ApoEε4 (y) |
| 2) ApoE genotype | ||||
| Sundermann et al. (2015) | HIV+ with or without NCI (n = 54) vs. HIV−/Ctl (n = 33), N-back test for memory for all | Not specified | 1) N-Back test for memory | COMT (y) |
| 2) Genotype/SNPs for COMT | ||||
| Becker et al. (2015) | HIV+ with or without various degrees of NCI (n = 2,846) | PBMC or immortalized B cells | 1) HAND: NP testing and T-scores based on Frascati criteria | ApoEε4 (n) |
| 2) ApoE genotype | ||||
| Villalba et al. (2015) | HIV+ with or without various degrees of NCI (n = 267), all with history of alcohol use disorder | Whole blood | 1) Neurocognitive test battery2) Genotype PCR | DRD2 (y), DRD4 (y) |
| Total n in candidate-gene studies | HIV+ with or without NCI (n = 13,296) vs. HIV−/Ctl (n = 2,843) | |||
| Levine et al. (2012a) | HIV+ with or without various degrees of NCI/HAND/HAD (AAN and Frascati) (n = 1,287) | Not specified | 1) Neurocognitive decline: Domain T-scores; HAD: AAN; NCI: Frascati | None |
| 2) GWAS (∼2.5 million SNPs) | ||||
| Jia et al. (2017) | HIV+ with GDS < 0.5 (n = 684) or GDS > 0.5 (n = 366), with or without various degrees of HAND (Frascati), CN (n = 568), ANI (n = 359), MND (n = 92), HAD (n = 30) (total n = 1,050) | PBMC | 1) HAND: NCI defined by GDS GDS < 0.5 and GDS > 0.5, continuous GDS; Frascati | None for GDS-defined NCI and HAND; SH3RF3 (y) for GDS < 0.5 vs. GDS > 0.5; T-cell receptor α locus (y) for continuous GDS |
| 2) GWAS (SNPs) | ||||
| Hulgan et al. (2019) | HIV+ with GDS < 0.5 (n = 658) or GDS > 0.5 (n = 352), with or without various degrees of HAND (Frascati), CN (n = 553), HAND (n = 457) (total n = 1,010) | Whole blood | 1) HAND: NCI defined by GDS > 0.5, continuous GDS; Frascati | mtDNA copy number (y) with NCI defined by GDS > 0.5, continuous GDS and HAND |
| 2) GWAS (SNPs) and mtDNA sequencing | ||||
| Rawat et al. (2020) | Children: Discovery cohort: HIV+ with NCI; (CSA < 70; n = 217) or without NCI (CSA > 70; n = 247); Validation cohort 1: HIV+ (n = 394) vs. HIV-/Ctl (n = 214) Validation cohort 2: HIV+ (n = 357) | PBMC | 1) CSA2) WES for identification of SNVs associated with NCI | CCRL2 (y); RETREG1/FAM134B (y); YWHAH (y) |
| Total n in GWAS/WES studies | HIV+ with or without NCI (n = 4,543) vs. HIV−/Ctl (n = 214) | |||