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Infectious Disease and Neurocognition
dysfunction (Eggers et al., 2017). In fact, HIV- associated neurocognitive impairment may present earlier during HIV now than it did before the introduction of antiretroviral therapy (Eggers et al., 2017). According to the results of one study, people
living with HIV who had been on antiretroviral therapy for a minimum of 15 years
(average duration of treatment was 20.3 years) were more likely to have cognitive
and mood problems than were controls. Moreover, compared to controls, the people
with HIV had decreased volume of subcortical gray matter and evidence of continuing neuronal damage and inammation (McMahan et al., 2023).
Common cognitive abnormalities in HIV- associated neurocognitive disorder include decits in concentration, attention, memory, psychomotor processing (Eggers
et al., 2017), executive function, and praxis. Focal or generalized seizures can occur
in approximately 5– 10 percent of people with HIV- associated neurocognitive impairment (Eggers et al., 2017). A meta- analysis found that the prevalence of newonset seizures in those infected with HIV was approximately 6.2 percent, which is
ve times higher than in the general population (Ssentongo, 2019). is review also
found that general seizures were more likely than focal seizures and that in addition
to HIV causing seizures (estimated at 32 percent), many with HIV may have opportunistic infections (e.g., toxoplasmosis and cryptococcus), which may by themselves
increase the risk for seizures. When considering cognitive dysfunction in HIV, it is
important to keep in mind that epilepsy alone is associated with cognitive dysfunction and so could contribute to the cognitive function seen in people living with HIV
who also have epilepsy.
Several factors associated with HIV could aect cognitive function in people
living with HIV. One contributing factor to HIV- associated cognitive dysfunction is
cerebral small- vessel disease (Deike et al., 2023). HIV also appears to accelerate brain
aging, which could result in people with HIV progressing toward dementia earlier
than the non- HIV population (Deike et al., 2023). In addition to cerebral smallvessel disease, HIV infection has been associated with dopamine function, one potential mechanism of which could involve the HIV- associated protein transactivator
of transcription, which might aect the dopamine transporter (Gaskill et al., 2017).
Neuroinammation associated with HIV may decrease neurogenesis, which
could be related to the neurocognitive decits associated with HIV (Katuri et al.,
2019). Interestingly, the degree of HIV- associated neurocognitive impairment may
not correlate with CD4+ count (Eggers et al., 2017; Paolillo et al., 2020), although in
their meta- analysis, Wang et al. (2020) found an association between the CD4+ level
and the prevalence of HAND in people with HIV. e apparent diusion coecient,
an indicator of microscopic brain changes, is elevated in the brains of people with
HAND. In discussing the etiology of HAND, Law- Ye et al. (2022) suggest that the
cognitive dysfunction seen in HIV could be due to direct eects from the HIV virus,
neuroinammation, toxicity from certain antiretroviral medications themselves, or
viral proteins.
Risk factors associated with HAND suggest other mechanisms by which HIV infection might aect cognitive function and include increased age, lower educational
Human Immunodeficiency Virus 79
attainment, lower CD4+ count, longer disease duration, more advanced disease
stage, presence of depression, higher levels of stress, medical comorbidities including neurological disorder and obesity, and poor medication adherence (Zenebe
et al., 2022).
While cognitive disorders in patients living with HIV are common, several interventions can ameliorate some of these symptoms. In this regard, both pharmacological and non- pharmacological approaches could be useful in treating the cognitive
decits associated with HIV. Antiretroviral drugs themselves can improve, even if
they do not entirely eliminate, the cognitive decits associated with HIV, and overall
they have signicantly reduced the incidence of HIV- associated dementia (Cliord
& Ances, 2013). In addition, treatment of infections comorbid with HIV such as
hepatitis C virus also has the potential to improve cognitive function. Proper treatment of HIV- associated depression has the potential to improve cognitive function
in people living with HIV. In addition to pharmacological interventions to improve cognition, other approaches shown to have a positive eect include exercise
programs and cognitive rehabilitation (Chan et al., 2020).
HIV- associated neuropsychiatric illnesses
Depression
Despite the availability and use of antiretroviral treatment, depression remains
common in people living with HIV, aecting approximately 30– 60 percent of people
with HIV. e etiology of depression in people living with HIV is likely complex and
could include a range of psychosocial factors such as stigmatization, marginalization, and loneliness and possibly factors related to HIV- induced brain inammation.
Further, HIV- associated depression also could cause or exacerbate the cognitive dysfunction associated with HIV. An antiretroviral used to treat HIV, efavirenz, is also
associated with depression in some people (Deike et al., 2023). Finding that 42 percent of their sample with cART- treated HIV had depressive symptom, Tymchuk et al.
(2018) also observed that that depressive symptoms were not associated with either
immunosuppression or HAND but rather quality of life related to health, quality of
sleep, and unemployment. Further, HIV- associated neurocognitive disorder can be
associated with depression (Eggers et al., 2017), making it important to rule out cognitive dysfunction in HIV patients with features of depression. HIV depression is
characterized by diculties solving problems, appetite problems, sleep dysfunction,
and cognitive diculties (Arseniou et al., 2014). Depression symptoms and their severity have been linked to the extent of cognitive impairment, and studies have found
an association between viral load and depression severity (Paolillo et al., 2020). It
has also been suggested that depression may exacerbate the neuropathology associated with infection (Arseniou et al., 2014; Paolillo et al., 2020), and depression in
people with HIV has been linked to pathological changes in cortical and subcortical
Infectious Disease and Neurocognition
regions and white matter pathways (Arseniou et al., 2014). In addition, depression
in those with HIV has been linked to dysfunction of the hypothalamus– pituitary–
thyroid axis, the transactivator of transcription protein, cytokines, somatostatin
dysregulation, and altered serotonin synthesis (Arseniou et al., 2014).
e neurocognitive disorders associated with HIV can aect overall psychological function. e results of a scoping review of 15 studies found that people living
with HIV- associated neurocognitive disorder showed poorer psychological and
functional quality of life compared to people with HIV but without HIV- associated
neurocognitive impairment. Noting that there were few available studies that assessed quality of life of people with HIV and cognitive decits, the authors also found
that most of the studies had been done in people who had been treated with antiretroviral therapy only comparatively briey, as longer antiretroviral treatment could
be associated with a higher psychological and functional ratings of quality of life in
people living with HIV- associated neurocognitive impairment (Alford et al., 2021).
Apathy
Apathy is commonly associated with HIV infection and was one of the rst notable
symptoms observed in people with HIV (Babicz et al., 2021). Apathy has been associated with decisions regarding treatment and treatment adherence (Babicz et al.,
2021). e increased apathy in individuals with HIV is related to increased social
withdrawal and withdrawal from relationships, which can cause further emotional
impairment (Kamat et al., 2016). Apathy in HIV infection can manifest as a reduction
in goal- directed behavior, motor behavior, and emotional and cognitive motivation
(Kamat et al., 2013; Rabkin et al., 2000). Depression and apathy can be dierentiated in HIV (Babicz et al., 2021), and it has been suggested that a key dierence
between depression and apathy in HIV may be related to dierent brain regions,
with apathy being associated with the medial prefrontal cortex and deep subcortical areas and depression being associated with le- prefrontal and limbic systems
(Kamat et al., 2013). In one study using diusion tensor imaging in HIV patients,
apathy, independent of depression, was associated with changes in white matter
connecting frontal regions and the basal ganglia (Kamat et al., 2014). Furthermore,
some studies have suggested that apathy and depression may be independently associated with dierent aspects of cognitive function. For example, one study found
that apathy correlated with performance on measures of working memory, while depression correlated with choice reaction time (Castellon et al., 1998). Some studies
have found support for an association between apathy and cognitive function (Paul
et al., 2005; Shapiro et al., 2013), while other studies have not (Rabkin et al., 2000).
In one sample, disease duration but not CD4+ count was shown to correlate with apathy (Paul et al., 2005). Although another study did not nd a relationship between
apathy and disease duration or CD4+ count, it did nd that apathy was associated
with highest level of HIV RNA plasma (Shapiro et al., 2013). Some of the variability
Human Immunodeficiency Virus 81
between these studies is likely related to sample characteristics that might aect cognitive functioning, the tests used to measure of cognitive functioning, apathy, and
depression, and antiretroviral status. Still, apathy appears to be common in those
infected with HIV and needs to be considered.
Mania
People who contract HIV may be at an elevated risk for developing mania. NakimuliMpungu et al. (2009) found that in people with HIV, accompanying mania was associated with middle- aged women and lower socioeconomic status. In their study,
Nakimuli- Mpungu et al. (2009) also examined the dierences between bipolar
mania and secondary mania (i.e., mania that developed secondarily to HIV infection) and found that the participants with bipolar mania had earlier onset compared
to secondary mania. Researchers noted in their study that there was little dierence
between the demographics of marital status and education in comparison to the two
groups (Nakimuli- Mpungu et al., 2009). However, they did observe that people who
were HIV positive with bipolar mania were more susceptible to immune suppression and cognitive impairment in comparison to HIV positive participants with secondary mania (Nakimuli- Mpungu et al., 2009).
A case series of 19 individuals with HIV but no history of AIDS- related dementia
or mood disorder presenting with mania underwent a thorough clinical workup, and
18 of the 19 were treated in an inpatient setting (Ellen et al., 1999). Fiy- two percent
had abnormalities noted on neuroimaging, most commonly mild atrophy, though
none had an abnormal neurological examination. ese 19 cases were thought to
represent mania secondary to HIV infection and in some cases to HIV since many
potentially contributing factors such as other infections and the patient’s medical
and family history were ruled out. is cohort represented 1.2 percent of all patients
with HIV infection seen over the same period at this hospital and 4.3 percent of all
persons with AIDS evaluated there (Ellen et al., 1999). In a similar study, patients
with HIV infection presenting with mania were evaluated to determine if the timing
of onset based on CD4+ count (i.e., early dened as CD4+ > 200 versus late dened
as CD4+ < 200) was related to sociodemographic or clinical variables (Lyketsos
et al., 1997). Patients with later- onset (i.e., CD4+ < 200, cuto for AIDS) mania had
more manic symptoms and less of a family or personal history of mood disorders
compared to persons with early- onset mania. From these ndings, the authors concluded that late- onset mania is associated with more severe disease (i.e., AIDS),
more likely in those with psychomotor slowing, and more likely in those with AIDSrelated dementia (60 percent of those in the AIDS sample) (Lyketsos et al., 1997). We
note that both of these studies were carried out prior to the availability of cART.
e association between bipolar disorder and HIV infection is not completely understood and may be bi- directional in that persons with bipolar disorder may be at
increased risk of HIV infection (Angelino & Treisman, 2008).
Infectious Disease and Neurocognition
Psychosis
ose with HIV infection appear to be at risk for developing psychosis. In a small
study (n = 22) of rst- episode psychosis, HIV- positive patients tended to show more
paranoia, more diculty with attention and concentration, and less aective disturbance than the rst- episode psychosis patients who were HIV negative (De Ronchi
et al., 2006), ndings suggesting that psychosis associated with HIV might have
some unique aspects compared to other types of psychosis.
Furthermore, the population of people living with HIV who had associated psychosis was oen associated with AIDs dementia, and the most common symptoms
included grandiose paranoid delusions with both auditory and visual hallucinations, as well as uctuations of moods such as depression and euphoria (Sewell,
1996). ere are several proposed hypotheses as to why there is this correlation with
HIV and associated psychosis. One theorizes that it could be a secondary eect of
HIV encephalopathy (Sewell, 1996). Another proposed theory included the nding
that the HIV coat protein increased the production of intraneuronal free calcium,
which could alter neurotransmitters that could induce psychotic and manic symptoms (Sewell, 1996). People with HIV and psychosis show greater impairment compared to other individuals with HIV and no psychotic symptoms (Laher et al., 2018).
Similarly, in one study of 478 patients in Uganda diagnosed with psychosis, those
that were also HIV positive (n = 156) were more impaired on a variety of cognitive
measures (Nakasujja et al., 2012). Other ndings from this study included the observation that most cases of psychosis in those with HIV were related to mania rather
than depression or schizophrenia and that women were more likely to demonstrate
cognitive impairment than were men (Nakasujja et al., 2012).
A recent systematic review and meta- analysis of studies carried out in Africa
found a high prevalence of HIV in those with rst- episode psychosis and a high prevalence of psychosis in those persons with HIV (Chhagan et al., 2021). For example,
a pooled estimated from three studies demonstrated the prevalence of psychotic
symptoms and psychosis in those infected with HIV to be 23 percent (Chhagan
et al., 2021). However, while some of these studies used formal assessment measures (Petrushkin et al., 2005), others used criteria from the Diagnostic and Statistical
Manual of Mental Disorders (Sall et al., 2009). Overall, the meta- analysis suggested
a signicant need for higher quality and quantity of studies in this important area of
research (Chhagan et al., 2021).
Conclusion
Despite the advent of cART, cognitive dysfunction aects approximately 42 percent
of people living with HIV. While the cognitive dysfunction associated with HIV is
asymptomatic in approximately 23 percent of people living with HIV, it is mild in
another approximately 13 percent, and 5 percent of people living with HIV have
Human Immunodeficiency Virus 83
HIV- associated dementia (Wang et al., 2020). Further, over 16 million people globally have some form of HIV- associated neurocognitive disorder, most of whom live
in Africa and Latin America (Wang et al., 2020). In addition to its associations with
cognitive dysfunction, HIV also elevates the risk for depression, apathy, mania, and
psychosis. ese associations with neurocognitive decits and neuropsychiatric
function in conjunction with the large number of people living with HIV indicate
that HIV results in a substantial global burden of neurocognitive and neuropsychiatric disease, particularly in African and Latin- American regions, and emphasizes
the need for continued treatment development for the decits in neurocognitive and
neuropsychiatric associated with HIV.
Acknowledgments
We are grateful to Hannah Kharazi who was extremely helpful with searching for,
nding, and procuring relevant research papers.
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7
Neurocognitive, Neuropsychiatric, and
Neurological Aspects of Human T- Cell
Lymphotropic Virus Type 1
Lance D. Erickson and Dawson W. Hedges
Introduction
e rst retrovirus discovered (Saito, 2019), human T- cell lymphotropic virus
type 1 (HTLV- 1) has been associated with both malignancy and neurological disease (Nagai & Osame, 2003), as well as with cognitive dysfunction and depressive
symptomology (Gascón et al., 2017). In this chapter, we explore the emerging research ndings that associate HTLV- 1 seropositivity with cognitive and neuropsychiatric disease, keeping in mind that these associations are likely dependent not only
on HTLV- 1 seropositivity itself but also on host immunological responses (Nagai
& Osame, 2003) and possibly on host sociodemographic circumstances (Erickson
et al., 2021). While this chapter is not meant to be a comprehensive treatment of
HTLV- 1, we do aim to provide an assessment of associations between HTLV- 1 and
neurological, cognitive, and neuropsychiatric disease.
A member of the Retroviridae family (Araujo, 2015), HTLV- 1 is endemic in southwestern Japan, sub- Saharan Africa, parts of Australo- Melanesia, parts of the Mid
East, Romania, and parts of South America, including Colombia, French Guyana
(Gessain & Cassar, 2012), and Brazil (de Carvalho et al., 2009). In areas where
HTLV- 1 is endemic, its prevalence can be quite high. In rural Gabon, for example,
the prevalence of HTLV- 1 is 12 percent (Caron et al., 2018). Furthermore, clusters
of infection can border regions of low HTLV- 1 seroprevalence (Gessain & Cassar,
2012). Primary modes of transmission of HTLV- 1 appear to be mother to child particularly in the context of prolonged breast feeding, sexual transmission particularly
from men to women, and from blood transfusions. e seroprevalences of HTLV- 1
increases with age particularly in women (Araujo, 2015) and is related to socioeconomic status. HTLV- 1 is estimated to aect approximately 5– 10 million people globally, although it is likely that this is an underestimate of the true global burden of
HTLV- 1 (Gessain & Cassar, 2012), making HTLV- 1 a signicant clinical and public
health problem particularly in regions where it is endemic.
Lance D. Erickson and Dawson W. Hedges,
In: Infectious Diseases in Neurocognitive and Neuropsychiatric Medicine
Oxford University Press. © Oxford University Press 2024. DOI: 10.1093/ oso/
Human T-Cell Lymphotropic Virus Type 1 87
Although most people infected with HTLV- 1 are asymptomatic (Araujo, 2015;
Nagai & Osame, 2003), HTLV- 1 has been associated with adult T- cell leukemia
and human T- cell lymphotropic virus type 1- associated tropical spastic paraparesis (HAM/ TSP) (Nose et al., 2006), as well as with decits in cognitive function
(Gascón et al., 2017). However, not all people seropositive for HTLV- 1 and yet considered asymptomatic are necessarily truly asymptomatic. Using a sample from
Brazil, Haziot et al. (2019) found that 42 out of 175 patients seropositive for HTLV- 1
but not diagnosed with HAM/ TSP had some sort of clinical abnormality, including
neurological and visual ndings, suggesting that the prevalence of truly asymptomatic carriers of HTLV- 1 might be lower than previously thought. Treatment for
HTLV- 1 infection is symptomatic, and there is no known cure (Rocha- Filho &
Goncalves, 2018).
HTLV- 1- associated tropical spastic paraparesis
In addition to its associations with adult T- cell leukemia (Gessain & Cassar, 2012),
HTLV- 1 is associated with HAM/ TSP, a slowly deteriorating (Araujo, 2015) myelopathy that occurs in approximately 0.2– 3 percent of people infected with HTLV1 (Grith et al., 2006). In a murine model, HTLV- 1 infection was associated with
motor abnormalities (Moghadam et al., 2018). In humans, risk factors for HAM/
TSP include a high proviral load and certain human leukocyte antigen variants
(Araujo, 2015). Clinically, HAM/ TSP is characterized by hyperreexia, motor weakness, leg spasticity, and problems with urination. Postural balance as assessed by a
force- platform evaluation found that patients with HAM/ TSP had worse postural
control compared to healthy controls, with patients seropositive for HTLV- 1 but not
with HAM/ TSP having postural control intermediate between the HAM/ TSP group
and the control group (Vasconcelos et al., 2019). Emphasizing the motor abnormalities in humans and because of some overlapping neurological ndings with other
diseases, HAM/ TSP can sometimes be dicult to distinguish from multiple sclerosis (Champs et al., 2013).
Numerous human leukocyte antigen genes and genes not related to human leukocyte antigens are associated with HTLV- 1 (Nose et al., 2006). HTLV- 1 infection
in children without overt HAM/ TSP in a sample from Peru was associated with
pyramidal tract and neuromuscular disease, which the authors thought could be a
precursor to HAM/ TSP (Kendall et al., 2009). A study from southern Japan found
that increased deep tendon reexes were associated with higher odds of developing
HAM/ TSP as calculated from a logistic regression model developed to predict
the occurrence of HAM/ TSP, suggesting spinal involvement in otherwise asymptomatic carriers of HTLV- 1. However, sex, family history of HAM/ TSP, and adult
T- cell leukemia were not associated with HAM/ TSP in the high- odds group (Nose
et al., 2006). As HAM/ TSP occurs only in a small minority of people infected with
HTLV- 1, genetically based host immune factors or dierent HTVL- 1 subtypes likely