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Infectious Disease and Neurocognition
Mean IQ Score +/- SE
PRE
PRE
TERM
120
110
100
90
80
70
60
Figure 5.4 Mean intelligence quotient (IQ) scores for term- born and preterm- born children
without and with an early postnatal infection with cytomegalovirus. Error bars indicate
standard errors (SEs). * p < 0.05.
Source: Brecht, K. F., Goelz, R., Bevot, A., Krägeloh- Mann, I., Wilke, M. & Lidzba, K. 2015. Postnatal human
cytomegalovirus infection in preterm infants has long- term neuropsychological sequelae. J Pediatr, 166,
834– 839.e1. Reprinted with permission from Elsevier.
*
*
CMV-
CMV+
seropositive for HCMV. Assessment of IQ utilized the Wechsler Abbreviated Scale of
Intelligence. Comparison of the IQ scores between HCMV antibody response were
for those who were HCMV- positive (mean IQ score: 91) and HCMV- negative (mean
IQ score: 110) (Figure 5.5), a dierence of 19 points that was statistically signicant
(p < 0.001). Additional subgroup analysis revealed that HMCV- positive patients had
lower performance (p = 0.001) and lower verbal (p = 0.049) IQ scores compared to
HCMV- negative patients. e result of this study indicates that adolescent patients
with schizophrenia spectrum disorders who are HCMV- positive are more likely to
have a lower IQ (Calkova et al., 2022).
It is surprising to know that disease burden due to cCMV infection is higher than
other more recognized childhood diseases; in fact, it is a principal cause of hearing
loss and neurological disability in children (Jones et al., 2023; Retzler et al., 2019).
Recent modeling in the United Kingdom of both direct costs (e.g., hospital) and indirect costs (e.g., personal) associated with the initial management of cCMV and the
resulting long- term consequences were extremely high (Retzler et al., 2019). e study
estimated the average total cost of cCMV in 2015; I updated the gures adjusting for
ination to 2023. In a single year, in the United Kingdom, the total cost to society of
cCMV is over a billion dollars (1,185,692,880 US dollars). e majority of the costs
(60 percent) were associated with personal costs (e.g., lost productivity), and the
70
100
110
120
130
100
110
120
130
Cytomegalovirus 69
90
80
70
CMV+ (N = 6) CMV- (N = 11)
90
80
Figure 5.5 Age- and sex- adjusted intelligence quotient (IQ) means with 95% confidence
intervals (analysis of covariance) in cytomegalovirus (CMV) immunoglobulin G (IgG)
seropositive (CMV+ ) and seronegative (CMV- ) adolescent patients with early- onset psychosis.
A scatter plot with median lines (93 and 108 for CMV+ and CMV- patients, respectively; Mann
Whitney U test, p = 0.001) is also presented. *** p < 0.001.
Source: Calkova, T., Cervenka, S., Yolken, R. H., Andreassen, O. A. & Andreou, D. 2022. Cytomegalovirus infection
associated with lower IQ in adolescent patients with schizophrenia spectrum disorders: A preliminary report.
J Psychiatr Res, 151, 571– 574. https:// doi.org/ 10.1016/ j.jps ychi res.2022.05.036, https:// crea tive comm ons.org/
licen ses/ by/ 4.0/
remaining 40 percent were costs to the healthcare system. Not surprisingly, the longterm sequelae accounted for the highest proportion of total costs for cCMV compared
to the initial management (Retzler et al., 2019). Given these enormous costs to society,
there should be greater urgency associated with vaccine development to prevent disease transmission and screening strategies to reduce overall morbidity and mortality.
Infectious Disease and Neurocognition
ese studies within the pediatric population emphasize the potential long- term
sequelae associated with cCMV infection (Retzler et al., 2019). Moreover, these ndings
highlight the importance of pediatric surveillance for cCMV in addition to education and
prevention programs (Engman et al., 2008; Teutsch et al., 2023; Wright & Permar, 2015).
Adult population
Dementia
e suggestion of a relationship between HCMV and Alzheimer’s disease (AD) has
been around for more than four decades (Renvoize et al., 1979). An early study compared 113 AD patients to 39 non- dementia controls and failed to show a statistically
signicant dierence in HCMV antibody titers (> 1/ 16) (Renvoize & Hambling,
1984). While the study did show that there were more AD patients with raised CMV
antibody titers compared to controls (85.84 versus 76.92 percent), the dierence was
not statistically signicant (p > 0.1), leading the authors to conclude that it is unlikely that CMV plays any role in AD.
Almost 20 years later, however, a postmortem study from the United Kingdom
that compared individuals who had vascular dementia with age- matched controls
found a statistically signicant 26- fold increase in CMV rates identied in brain
tissue (odds ratio (OR): 26.6, 95 percent CI: 3.04– 232.6, p = 0.0002) (Lin et al., 2002).
Ninety- three percent of the patients with vascular dementia had CMV in brain
tissue compared to 34 percent of the normal controls.
In another study, 58 HCMV- positive deceased patients and 39 HCMV- negative
deceased controls from the Rush Alzheimer’s Disease Center Religious Orders Study
were compared in terms of three diagnostic groups: (1) no cognitive impairment,
(2) mild cognitive impairment, and (3) probable AD just before death (Lurain et al.,
2013). When those who were CMV- positive (n = 58) were compared with those who
were CMV- negative (n = 39) in terms of mild cognitive impairment, there was an
increased association (OR: 1.62, 95 percent CI: 0.64– 4.09), but it was not statistically signicant. When comparing CMV- positive with CMV- negative individuals
with AD, there was a decreased likelihood of an association (OR: 0.90, 95 percent
CI: 0.38– 2.14), which was also not statistically signicant. A contributing factor to
these results was likely the small sample size of the study. is study was criticized
for not using brain tissue and instead relying on peripheral tissue reiterating that
unless CMV was identied in brain tissue itself the results provide no evidence for a
relationship between HCMV and AD (Itzhaki & Klapper, 2014).
A prospective study from the United States combined three cohorts with a total
of 849 individuals with a mean age of 78.6 years (±SD: 7.2 years). One- quarter of the
overall sample were African American (Barnes et al., 2015). Serum CMV immunoglobulin (Ig)- G antibodies were compared between the groups; overall, almost threequarters (73.4 percent) had evidence of prior CMV exposure. African Americans had
Cytomegalovirus 71
68.2 percent, p < 0.001). roughout the 5- year follow- up period, 93 individuals developed AD, with CMV- positivity increasing the risk of developing AD (relative
risk: 2.15, 95 percent CI: 1.42– 3.27), which was statistically signicant. Aer adjusting
for potential confounding factors (e.g., age, sex, education, race, vascular risk factors
and diseases, and genetic factors such as the apolipoprotein E epsilon 4 level), the result did not change (relative risk: 2.24, 95 percent CI: 1.48– 3.39, p < 0.001) (Barnes
et al., 2015). Moreover, those individuals who were CMV- positive and developed AD
had a more rapid decline in their global cognition score (−0.02 ± 0.01; p = 0.03). e
ndings from this study suggest that CMV is associated with an increased risk of developing AD and with a more rapid decline in cognitive status (Barnes et al., 2015).
A Korean study conducted using the National Health Insurance Database based on
International Classication of Disease codes identied 687 individuals over the age
of 40 years who were CMV- positive and compared them to a CMV- negative group of
3435 individuals (matched for age and sex) (Lee et al., 2020). ose who were CMVpositive were almost two times more likely to have developed dementia (OR: 1.90,
95 percent CI: 1.20– 2.80). In addition, those who were CMV- positive were even
more likely to develop vascular dementia (OR: 2.9, 95 percent CI: 1.10– 7.50) compared to AD (OR: 1.60, 95 percent CI: 1.00– 2.60). ere was an interesting nding
where those aged 40– 59 years who were CMV- positive were substantially more likely
to develop any type of dementia (OR: 11.7, 95 percent CI: 2.50– 49.40) compared to
those age 60– 79 years (OR: 1.80, 95 percent CI: 1.10– 3.20) and over 80 years of age
(OR: 1.30, 95 percent CI: 0.50– 2.80) (Lee et al., 2020). ese models were adjusted for
the following potential confounding factors: age, sex, low income, body mass index,
transplantation status, malignant neoplasms, end- stage renal disease on dialysis, type
2 diabetes mellitus, hypertension, and dyslipidaemia. Additional research is required
to further clarify the association between HCMV infection and dementia.
Psychiatric illness
HCMV has also been linked to certain psychiatric conditions, primarily anxiety, depression, and schizophrenia. An important question when considering associations
between HCMV and neuropsychiatric disorders is whether stress can result in reactivation of HCMV leading to neuropsychiatric illness.
A cross- sectional study from the United States assessed 139 individuals with bipolar disorder (BD) (mean age: 39 years, 63 percent female) based on Diagnostic
and Statistical Manual of Mental Disorders, fourth edition (DSM- IV) criteria and 99
healthy controls (mean age: 32 years, 51 percent female) in terms of their HCMV IgG
antibody status (Prossin et al., 2015). ose with BD had higher antibody concentrations than did healthy controls (3.0 versus 2.1, p = 0.002) (Figure 5.6). Subgroup
analysis reported that CMV IgG antibody levels were higher among those with elevated moods (p < 0.03) but no dierent for those with depressed moods (p > 0.10)
(Prossin et al., 2015). A limitation of the study was the cross- sectional design: further studies attempting to replicate the results would need to determine if reactivation of CMV infection intensies BD mood states.
Infectious Disease and Neurocognition
Mean CMV IgG concentration
Diagnosis
4.000
3.000
2.000
1.000
0.000
Figure 5.6 Graphical depiction of diagnostic dierences in cytomegalovirus (CMV) antibody
concentrations. Standardized mean antibody (immunoglobulin G (IgG)) concentrations are
depicted on the vertical y- axis and diagnosis on the horizontal x- axis. CMV IgG concentration
was higher in BD- I volunteers (shown in maize color) as compared to healthy control volunteers
(shown in blue color), Error bars represent ±1 standard error.
Source: Prossin, A. R., Yolken, R. H., Kamali, M., Heitzeg, M. M., Kaplow, J. B., Coryell, W. H. & McInnis, M. G. 2015.
Cytomegalovirus antibody elevation in bipolar disorder: Relation to elevated mood states. Neural Plast, 2015,
939780. https:// doi.org/ 10.1155/ 2015/ 939 780, https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
Healthy controls
Bipolar disorder type 1
Another study tested the hypothesis that early- life stress could be linked to
activating HCMV and be associated with major depressive disorder (Ford et al.,
2019). is study used a discovery sample of 179 individuals diagnosed with major
depressive disorder based on DSM- IV criteria (mean age: 36 years, 77 percent female) and a replication sample of 295 individuals diagnosed with major depressive
disorder based on DSM- 5 criteria (mean age: 35 years, 62 percent female). e prevalence of HCMV IgG antibodies in the discovery sample was 45.3 percent compared
to those from the replication sample, which was 56.0 percent seropositive for HCMV.
e analysis involved a logistic regression model adjusting for age, sex, and ethnicity.
ose with greater early- life stress were more likely to be HCMV- positive (OR: 1.02,
95 percent CI: 1.00– 1.04, discovery sample, and OR: 1.02, 95 percent CI: 1.01– 1.03,
replication sample) (Ford et al., 2019). e ndings suggest that early- life stress may
be associated with HCMV status and subsequent reactivation; however, the magnitude of the point estimates was not very impressive, and further research is required.
A recent Finnish cohort study (n = 8028) aimed to determine if HCMV status
could predict the development of new- onset anxiety and depression (Markkula
et al., 2020). e sample consisted of a representative sample of individuals aged over
30 years who had HCMV IgG antibodies measured. ere was an 11- year follow- up
of the cohort to determine how many developed new- onset anxiety and depression
disorders based on a diagnostic interview. e main nding from this study was that
Cytomegalovirus 73
those individuals who were HCMV- positive at baseline were less likely to develop
new- onset anxiety disorder (OR: 0.43, 95 percent CI: 0.22– 0.86) (Markkula et al.,
2020). is model adjusted for age, sex, educational level, region of residence, and
marital status. is study did not nd a link between baseline HMCV infection and
the subsequent development of anxiety or depression.
A cross- sectional study aimed to determine the relationship between HCMV and depression using data from the National Health and Nutrition Examination Survey (Gale
et al., 2018). Information from the survey included depression status of individuals, antidepressant use, HCMV status, and general demographic factors (mean age: 30 years,
51 percent female). e model adjusted for age, sex, socioeconomic status, race/ ethnicity,
education level, smoking status, and sexual behavior (i.e., sexually transmitted infection).
Individuals with a high HCMV antibody level (n = 891) were more likely to have depression (OR: 1.56, p = 0.06), but this was not statistically signicant. ese results suggest
that the link between HCMV and depression may also aect younger individuals (Gale
et al., 2018), although additional research evaluating this association is required.
A recent study investigated the relationship between HCMV antibodies and
BD (n = 87), depression (n = 85), suicide (n = 119), and schizophrenia (n = 114),
using brain tissue from postmortem examinations (Zheng et al., 2023). ose with
a positive HCMV antibody response were more likely to have had BD (OR: 2.45,
95 percent CI: 1.24– 4.93), major depression (OR: 3.70, 95 percent CI: 1.84– 7.74), suicide (OR: 2.09, 95 percent CI: 1.27– 3.48), and schizophrenia (OR: 1.40, 95 percent
CI: 0.75– 2.65) (Zheng et al., 2023), although the association with schizophrenia was
not signicant. e results raise the possibility that the reactivation of HCMV may
be related to increased neuroinammation resulting in the subsequent development
of these psychiatric disorders.
Conclusion
HCMV infection appears to play a role in the development of neurocognitive decits
among children and adults and dementia in adulthood. Given that HCMV is such a
ubiquitous infection in the human population, it can be dicult to see the forest for
the trees when trying to determine the role of the infection to any neurocognitive
disorder, neurodevelopmental disorder, or dementia. Large sample sizes, prospective study design, and critical assessment of potential confounding factors will be
vitally important in determining the role of HCMV in these debilitating conditions
with lifelong morbidity and potential mortality.
References
AL MANA, H., YASSINE, H. M., YOUNES, N. N., AL- MOHANNADI, A., AL- SADEQ, D. W.,
ALHABABI, D., NASSER, E. A. & NASRALLAH, G. K. 2019. e current status of cytomegalovirus
(CMV) prevalence in the MENA region: A systematic review. Pathogens, 8, 213.
Infectious Disease and Neurocognition
BARNES, L. L., CAPUANO, A. W., AIELLO, A. E., TURNER, A. D., YOLKEN, R. H., TORREY, E. F. &
BENNETT, D. A. 2015. Cytomegalovirus infection and risk of Alzheimer disease in older black and
white individuals. J Infect Dis, 211, 230– 237.
BRECHT, K. F., GOELZ, R., BEVOT, A., KRÄGELOH- MANN, I., WILKE, M. & LIDZBA, K. 2015.
Postnatal human cytomegalovirus infection in preterm infants has long- term neuropsychological
sequelae. J P edi atr, 166, 834– 839.e1.
CALKOVA, T., CERVENKA, S., YOLKEN, R. H., ANDREASSEN, O. A. & ANDREOU, D. 2022.
Cytomegalovirus infection associated with lower IQ in adolescent patients with schizophrenia spectrum disorders: A preliminary report. J Psychiatr Res, 151, 571– 574.
CANFIELD, D., GABBY, L., VAZIRI FARD, E. & GYAMFI- BANNERMAN, C. 2023. Cytomegalovirus
in pregnancy. Obstet Gynecol Clin North Am, 50, 263– 277.
CANNON, M. J., SCHMID, D. S. & HYDE, T. B. 2010. Review of cytomegalovirus seroprevalence and
demographic characteristics associated with infection. Rev Med Virol, 20, 202– 213.
COX, F., MEYER, D. & HUGHES, W. T. 1975. Cytomegalovirus in tears from patients with normal eyes
and with acute cytomegalovirus chorioretinitis. Am J Ophthalmol, 80, 817– 824.
CRAWFORD, L. B., DIGGINS, N. L., CAPOSIO, P. & HANCOCK, M. H. 2022. Advances in model sys-
tems for human cytomegalovirus latency and reactivation. mBio, 13, e0172421.
DELFORGE, M. L., COSTA, E., BRANCART, F., GOLDMAN, D., MONTESINOS, I., ZAYTOUNI, S.,
MARCHANT, A. & DONNER, C. 2017. Presence of cytomegalovirus in urine and blood of pregnant
women with primary infection might be associated with fetal infection. J Clin Virol, 90, 14– 17.
DIOVERTI, M. V. & RAZONABLE, R. R. 2016. Cytomegalovirus. Microbiol Spectr, 4, 10.1128/
microbiolspec.DMIH2- 0022- 2015.
ENGMAN, M. L., MALM, G., ENGSTROM, L., PETERSSON, K., KARLTORP, E., TEAR
FAHNEHJELM, K., UHLEN, I., GUTHENBERG, C. & LEWENSOHN- FUCHS, I. 2008. Congenital
CMV infection: Prevalence in newborns and the impact on hearing decit. Scand J Infect Dis, 40,
935– 942.
FORD, B. N., YOLKEN, R. H., AUPPERLE, R. L., TEAGUE, T. K., IRWIN, M. R., PAULUS, M. P. &
SAVITZ, J. 2019. Association of early- life stress with cytomegalovirus infection in adults with major
depressive disorder. JAMA Psychiatry, 76, 545– 547.
GALE, S. D., BERRETT, A. N., ERICKSON, L. D., BROWN, B. L. & HEDGES, D. W. 2018. Association
between virus exposure and depression in US adults. Psychiatry Res, 261, 73– 79.
GOODRUM, F. 2022. e complex biology of human cytomegalovirus latency. Adv Virus Res,
112, 31– 85.
HANDSFIELD, H. H., CHANDLER, S. H., CAINE, V. A., MEYERS, J. D., COREY, L., MEDEIROS, E.
& MCDOUGALL, J. K. 1985. Cytomegalovirus infection in sex partners: Evidence for sexual transmission. J Infect Dis, 151, 344– 348.
HU, X., HU, W., SUN, X., CHEN, L. & LUO, X. 2021. Transmission of cytomegalovirus via breast milk
in low birth weight and premature infants: A systematic review and meta- analysis. BMC Pediatr,
21, 520.
ITZHAKI, R. F. & KLAPPER, P. 2014. Cytomegalovirus: An improbable cause of Alzheimer disease. J
Infect Dis, 209, 972– 973.
JONES, C. E., BAILEY, H., BAMFORD, A., CALVERT, A., DOREY, R. B., DRYSDALE, S. B., KHALIL,
A., HEATH, P. T., LYALL, H., RALPH, K. M. I., SAPUAN, S., VANDREVALA, T., WALTER, S.,
WHITTAKER, E., WOOD, S. & UK CONGENITAL CMV INFECTION COLLABORATION
(UKCCIC). 2023. Managing challenges in congenital CMV: Current thinking. Arch Dis Child, 108,
601– 607.
KOKKOLA, E., NIEMENSIVU, R., LAPPALAINEN, M., PALOMAKI, M., NIEMINEN, T.,
BOPPANA, S., SAXEN, H. & PUHAKKA, L. 2023. Long- term outcome of vestibular function and
hearing in children with congenital cytomegalovirus infection: A prospective cohort study. Eur Arch
Otorhinolaryngol, 280, 3141– 3147.
KRSTANOVIĆ, F., BRITT, W. J., JONJIC, S. & BRIZIC, I. 2021. Cytomegalovirus infection and inam-
mation in developing brain. Virus es, 13, 1078.
LANCINI, D., FADDY, H. M., FLOWER, R. & HOGAN, C. 2014. Cytomegalovirus disease in immu-
nocompetent adults. Med J Aust, 201, 578– 580.
Cytomegalovirus 75
LEE, K. H., KWON, D., LA, Y. D., LA, Y. & HAN, S. H. 2020. Association between cytomegalovirus
end- organ diseases and moderate- to- severe dementia: A population- based cohort study. BMC
Neurol, 20, 216.
LIN, W. R., WOZNIAK, M. A., WILCOCK, G. K. & ITZHAKI, R. F. 2002. Cytomegalovirus is present
in a very high proportion of brains from vascular dementia patients. Neurobiol Dis, 9, 82– 87.
LUPTON, J., VERNAMONTI, J., MCCABE, C., NOBLE, J., YIN, H. Z., EYRE, R. C. & KIESSLING, A.
A. 2014. Cytomegalovirus and human immunodeciency virus in semen of homosexual men. Fertil
Steril, 101, 350– 358.
LURAIN, N. S., HANSON, B. A., MARTINSON, J., LEURGANS, S. E., LANDAY, A. L., BENNETT, D.
A. & SCHNEIDER, J. A. 2013. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis, 208, 564– 572.
MARKKULA, N., LINDGREN, M., YOLKEN, R. H. & SUVISAARI, J. 2020. Association of exposure to
Toxoplasma gondii, Epstein– Barr virus, herpes simplex virus type 1 and cytomegalovirus with newonset depressive and anxiety disorders: An 11- year follow- up study. Brain Behav Immun, 87, 238– 242.
MAYER, B. T., KRANTZ, E. M., WALD, A., COREY, L., CASPER, C., GANTT, S. & SCHIFFER, J. T.
2020. Estimating the risk of human herpesvirus 6 and cytomegalovirus transmission to Ugandan infants from viral shedding in saliva by household contacts. Viruses- Basel, 12, 171.
NJERU, D. G., MWANDA, W. O., KITONYI, G. W. & NJAGI, E. C. 2009. Prevalence of cytomegalo-
virus antibodies in blood donors at the National Blood Transfusion Centre, Nairobi. East Afr Med J,
86, S58– S61.
O’CONNOR, C. M. 2021. Cytomegalovirus (CMV) infection and latency. Pathogens, 10, 342.
PASS, R. F. & ANDERSON, B. 2014. Mother- to- child transmission of cytomegalovirus and prevention
of congenital infection. J Pediatric Infect Dis Soc, 3 Suppl 1, S2– S6.
PROSSIN, A. R., YOLKEN, R. H., KAMALI, M., HEITZEG, M. M., KAPLOW, J. B., CORYELL, W. H.
& MCINNIS, M. G. 2015. Cytomegalovirus antibody elevation in bipolar disorder: Relation to ele-
vated mood states. Neural Plast, 2015, 939780.
RENVOIZE, E. B. & HAMBLING, M. H. 1984. Cytomegalovirus infection and Alzheimer’s disease.
Age Ageing, 13, 205– 209.
RENVOIZE, E. B., HAMBLING, M. H., PEPPER, M. D. & RAJAH, S. M. 1979. Possible association of
Alzheimer’s disease with HLA- BW15 and cytomegalovirus infection. Lancet, 1, 1238.
RETZLER, J., HEX, N., BARTLETT, C., WEBB, A., WOOD, S., STAR, C., GRIFFITHS, P. & JONES, C.
E. 2019. Economic cost of congenital CMV in the UK. Arch Dis Child, 104, 559– 563.
SCHOTTSTEDT, V., BLUMEL, J., BURGER, R., DROSTEN, C., GRONER, A., GURTLER, L.,
HEIDEN, M., HILDEBRANDT, M., JANSEN, B., MONTAG- LESSING, T., OFFERGELD, R.,
PAULI, G., SEITZ, R., SCHLENKRICH, U., STROBEL, J., WILLKOMMEN, H. & VON KONIG, C.
H. 2010. Human cytomegalovirus (HCMV)— Revised. Transfus Med Hemother, 37, 365– 375.
SCHWARTZ, M. & STERN- GINOSSAR, N. 2023. Rethinking human cytomegalovirus latency reser-
voir. Ann N Y Acad Sci, 1524, 30– 36.
SILVA JUNIOR, H. T., TOKAT, Y., CAI, J., SINGH, I., SANDHU, A., DEMUTH, D. & KIM, J. 2023.
Epidemiology, management, and burden of cytomegalovirus in solid organ transplant recipients in selected
countries outside of Europe and North America: A systematic review. Transpl Infect Dis, 25, e14070.
SMITH, N. A., CHAN, G. C. & O’CONNOR, C. M. 2021. Modulation of host cell signaling during cyto-
megalovirus latency and reactivation. Virol J, 18, 207.
STEWART, A. G. & KOTTON, C. N. 2024. What’s new: Updates on cytomegalovirus in solid organ
transplantation. Transplantation, 108, 884– 897.
TEUTSCH, S. M., NUNEZ, C. A., MORRIS, A., ESLICK, G. D. & ELLIOTT, E. J. 2023. Australian
Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2022. Commun Dis Intell (2018),
47, 10.33321/ cdi.2023.47.46.
WRIGHT, C. J. & PERMAR, S. R. 2015. Preventing postnatal cytomegalovirus infection in the preterm
infant: Should it be done, can it be done, and at what cost? J P edia tr, 166, 795– 798.
ZHENG, H., WEBSTER, M. J., WEICKERT, C. S., BEASLEY, C. L., PAULUS, M. P., YOLKEN, R. H. &
SAVITZ, J. 2023. Cytomegalovirus antibodies are associated with mood disorders, suicide, markers
of neuroinammation, and microglia activation in postmortem brain samples. Mol Psychiatry, 28,
5282– 5292.
6
Human Immunodeficiency Virus
Martins Nweke, Dawson W. Hedges, and Shawn D. Gale
Introduction
First identied in the early 1980s (Boisse et al., 2008), human immunodeciency
virus (HIV) infects approximately 40 million people worldwide (UNAIDS, 2023). In
2022, there were an estimated 1.3 million new cases of HIV, of which 46 percent were
in girls and women. In sub- Saharan Africa, sixty- three percent of new cases are in
girls and women, whereas 70 percent of new cases in other global regions are in boys
and men. Although it remains substantial, the number of new HIV cases is declining
(UNAIDS, 2023). Since the introduction of combined antiretroviral therapy (cART)
in 1996, people living with HIV now can expect a nearly normal lifespan. Despite
the introduction and use of cART and improved lifespan of people living with HIV,
however, HIV remains incurable (Eggers et al., 2017). Even with the advent of cART,
HIV continues to be associated with neurocognitive and neuropsychiatric disorders
from opportunistic infections such as cytomegalovirus due to HIV- induced immunosuppression and from primary eects of HIV on the brain (Boisse et al., 2008).
HIV has complex deleterious inammatory, immune, and other eects that
may be relevant for and associated with the neuropsychiatric and cognitive eects
found in some patients with HIV. Although HIV may not directly infect neurons,
HIV- infected macrophages and microglial cells can cross the blood– brain barrier (Andhavarapu et al., 2020). Once in the brain, these macrophages and microglial cells can activate other immune cells (Andhavarapu et al., 2020). Overall,
HIV induces neuroinammation (Katuri et al., 2019). In addition to resulting in
neuroinammation, HIV alters calcium homeostasis, upsetting interactions between the endoplasmic reticulum, mitochondria, and autophagy, which contribute
to the neuropsychiatric and neurocognitive sequelae of HIV (Andhavarapu et al.,
2020). Moreover, HIV can remain viable and capable of replication in microglial
cells even with use of cART (Tang et al., 2023). In a small study, the group with untreated HIV had a 17 percent reduction in hemispheric volume and 29 percent fewer
oligodendrocytes compared to controls (Kaalund et al., 2019). Further, additional
atrophic changes, particularly in subcortical regions of the brain, can be observed
in persons with HIV (Kopstein & Mohlman, 2023; McMahan et al., 2023), ndings
that likely contribute to cognitive functioning, although there can be substantial
heterogeneity between persons (Devlin & Giovannetti, 2017). Still, the prevalence
Martins Nweke, Dawson W. Hedges, and Shawn D. Gale, Human Immunodeficiency Virus In:
Neuropsychiatric Medicine
© Oxford University Press 2024. DOI: 10.1093/ oso/ 9780192870414.003.0007
Human Immunodeficiency Virus 77
of neurocognitive dysfunction in people with HIV is high at approximately 42 percent, although most cases are asymptomatic or mild likely due to current treatments
such as cART (Wang et al., 2020). Unfortunately, there are regional disparities in
the prevalence of HIV- associated neurocognitive disorder (Wang et al., 2020). HIV
can also aect the peripheral nervous system (Boisse et al., 2008). us, HIV infection is associated with potential negative neurologic eects on many aspects of the
nervous system (Boisse et al., 2008). Furthermore, immunosuppression increases
the risk for opportunistic infections, some of which may aect neuropsychiatric or
neurocognitive functions in and of themselves, increase mortality and morbidity,
and complicate outcomes (Azoulay et al., 2020; Gale et al., 2016; Goldschmidt &
Chu, 2021; Hedges & Gale, 2022; Saloner et al., 2019; Zanoni & Gandhi, 2014).
HIV and neuropsychological functions
HIV- associated neurocognitive disorder
Although antiretroviral treatment has prolonged the lifespan of people living
with HIV, approximately 20– 50 percent of patients with HIV nevertheless have a
range of neurocognitive decits (Eggers et al., 2017; Zenebe et al., 2022). e most
common type of HIV- associated neurocognitive dysfunction (HAND) is asymptomatic neurocognitive impairment (Andhavarapu et al., 2020). By denition,
asymptomatic HAND does not impede activities of daily living (Cliord & Ances,
2013; Eggers et al., 2017). Still, asymptomatic neurocognitive impairment is observable on formal cognitive testing where performance is at least one standard
deviation below average in at least two cognitive domains (Cliord & Ances, 2013;
Eggers et al., 2017). Another type of HAND is considered mild (Andhavarapu et al.,
2020) with the remaining type of neurocognitive function being HIV- associated dementia (Andhavarapu et al., 2020). Asymptomatic neurocognitive impairment in
HIV can progress to mild neurocognitive impairment in people living with HIV, and
the prevalence of HIV- related neurocognitive impairment increases with increasing
age (Eggers et al., 2017). Estimates of the percentage of people living with HIV who
have HAND vary from 20 to 90 percent. According to the results of a 2020 metaanalysis of people living with HIV, HAND was present in 42.6 percent, with asymptomatic neurocognitive impairment occurring in approximately 23 percent, mild
neurocognitive impairment in approximately 13 percent, and HIV- associated dementia in approximately 5 percent, although there were limited data from many
countries. In total, there were an estimated 16,145,400 cases of HAND in adults with
HIV worldwide, with the majority living in sub- Saharan Africa (72 percent) and
Latin America (Wang et al., 2020).
e advances in the treatment of HIV oered by antiviral medication have decreased the prevalence of HIV- associated dementia but have not decreased the
incidence and prevalence of asymptomatic and mild HIV- associated cognitive