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HIV Infection
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This entry is adapted from the peer-reviewed paper 10.3390/brainsci11020248

HIV-1 (human immunodeficiency virus type 1) is one of the most dangerous and widespread infectious viruses and causes the deaths of millions of people. The global spread of this virus, which has taken on the character of a pandemic, has made HIV a central health problem worldwide. Currently, thanks to the active development of innovative forms of antiretroviral drugs and increased access to effective means of prevention, HIV infection has become a non-fatal, and in many cases, chronic disease. Thus, the life expectancy of people living with HIV  (PLWH) has significantly increased. At the same time, in the population of PLWH, in addition to the consistenly observed higher rates of morbidity and mortality from cardiovascular diseases, various metabolic complications, and non-AIDS-related malignancies, there is a clear trend towards the spread of neurocognitive disorders.

 

HIV-1 CNS CNS cells neurocognitive disorders (HAND)

1. Mental Disorders Associated with HIV Infection

The relationship between HIV infection and mental illness is rather complex and largely unexplored to date. It has been shown that people with severe mental disorders have a significantly increased risk of HIV infection [1][2]. It was also found that the percentage of HIV infection in patients with a mental pathology is, on average, seven times higher than that among mentally healthy people [1][2]. It is believed that this is due to the distortion of the processes of perception and thinking in persons suffering from mental disorders, their use of psychoactive substances, their risky sexual behavior, and sexual victimization [1][2]. Thus, it has been found that an increased risk of HIV infection is directly associated with hypersexuality during an exacerbation of mental illness. It was noted that the frequency of sexual activity in the acute phase of schizophrenia increased in 38.6% of individuals and in 44.8% of individuals with bipolar disorders, the frequency of sexual activity in individuals with mental illnesses under the influence of heroin increased in 43.4% [3]. Such patients had sexual behavior associated with an increased risk of sexual transmission of HIV: 39–42.7% had intercourse with several sexual partners at the same time; 24% had sex with prostitutes, and in doing so, 65% had unprotected sexual intercourse (of which 12.5% had unprotected sexual intercourse in order to earn money), [3][4]. Additionally, as a result of impaired cognitive abilities, evaluation, and judgment, people with mental disorders are much more likely to be at risk of coerced sex [3][4][5][6][7][8]. The frequency of forced sexual intercourse among this group of individuals is 10–38% [4][9][10]. Many patients with mental illnesses such as schizophrenia and bipolar disorder have been found to have experienced sexual abuse in childhood [7][9][11]. The traumatic experience is later reproduced in life and such persons repeatedly become victims of sexual violence; they are characterized by sexually promiscuous and risky sexual behavior in adulthood [7][12].

In turn, over the more than thirty years of the HIV epidemic, many materials have been accumulated indicating that HIV infection predisposes one to the development of a mental pathology such as anxiety disorders, bipolar disorders, schizophrenia, and cognitive disorders. It has been observed that the early stages of HIV infection are most often accompanied by a depressive state [13][14]. The progression of HIV infection is then characterized by the development of psychosis, adjustment disorder, and bipolar disorder [1][15][16]. In the African continent, where the burden of HIV infection is particularly high, the prevalence of HIV infection among adults with severe mental disorders ranges from 11 to 48.6% [17][18][19][20][21][22]. The results of a multisite study conducted in the United States showed that 36% of people living with HIV (PLWH) suffered from severe depression, 15.8% suffered from generalized anxiety disorder (GAD), and 10.5% suffered from panic disorder (PD)—three times higher than similar indicators among the general population [23][24][25]. At the same time, a combination of GAD and PD was diagnosed in 5% of PLWH [24]. Thus, it can be stated that HIV infection is a serious predictor of the development of severe forms of depression, GAD, and PD [26]. It should be noted that early initiation of antiretroviral therapy (ART) does not reduce the risk of any of these mental disorders. In India, the number of HIV-infected people with severe forms of depression is 59%, and in China, this number ranges from 32.9 to 85.6% [13][27][28][29]. It is found that depressive conditions in PLWH significantly increase the risk of death [30][31]. An analysis of the case histories of 5927 HIV-infected people showed that mild and short-term (1–4 days) depression and/or mild but more persistent depressive conditions can negatively affect the process of HIV treatment and the survival of PLWH [14].

It was revealed that psychosis is more often diagnosed in patients with severe immunodeficiency (CD4 ≤ 200–350 cells/mm3), which usually occurs in the late stages of HIV infection. The frequency of the first psychotic episodes in HIV-positive individuals ranges from 1 to 15% [32][33]. For psychoses arising in HIV-infected patients, hallucinations, affective disorders, cognitive impairments, and dementia are common [34][35]. Moreover, the risk of schizophrenia and acute psychosis in people infected with HIV during the first year after infection is quite high, with an incidence rate of 8.24 and 12.7, respectively [32]. Moreover, an increased risk of developing schizophrenia persists for more than 5 years after the diagnosis of an HIV infection, at which point the majority of PLWH receive antiretroviral therapy (ART), leading to suppression of viral replication and of opportunistic infections [32]. It was found that the comorbidity of HIV infection and schizophrenia among such patients significantly correlates with a high risk of lethal cases [16][32]. The results of two large-scale studies showed that among patients with schizophrenia, there was a higher mortality rate in the group of HIV-positive individuals compared to the group of HIV-negative patients [16][32]. A six-year follow-up of such patients revealed that the mortality among HIV-positive patients diagnosed with schizophrenia was 25.5%, while that among HIV-negative patients with the same diagnosis was only 17.8% [16]. Another more long-term (12-year) study found that the mortality rate in the group of patients with HIV and schizophrenia was 25.8, while in those with schizophrenia but not infected with HIV, this indicator was 6.24 [32].

According to the materials of the short international neuropsychiatric questionnaire (MINI), cases of bipolar disorder among PLWH in economically developed countries are 5.6–8.1%, which is 3–4 times higher than the same indicators among the general populations of these countries (2.1%) [36][37][38]. In developing countries, this figure reaches 30% [39]. Manic disorder in HIV-positive individuals during later stages of the infection often occurs as a phase of bipolar disorder and is likely associated with the direct effect of HIV on the cells of the central nervous system (CNS). Manic disorder can also result from a secondary infection or be influenced by ART. It was found that severe cognitive impairment occurred in 54.8% of people with HIV-associated mania, while in HIV-negative people with the initial stage of that same mental pathology, such disorders occurred in only 15.9% [29]. It was also shown that HIV-associated manic disorder represents the initial stage of HIV-associated dementia [49–51], which occurs in 10% of HIV-positive individuals during the late stages of HIV infection [40].

2. Biological Mechanisms of HIV-1—Effect on CNS Functions

It has now been proven that neurocognitive changes in HIV-positive individuals are the result of the direct effect of HIV on the central nervous system (CNS). It was found that following the first days after infection with human immunodeficiency virus type 1 (HIV-1), this viral agent penetrates into the tissues of the CNS [41] and localizes in the various parts of the brain [42][43]. Viral RNA was found in the caudate nucleus, the cortex of the frontal lobe of the brain, and the cerebrospinal fluid. HIV-1 localized in the basal ganglia of the CNS causes progressive neurodegenerative changes, as well as impaired neuromotor and neurocognitive functions. A number of studies have shown that the development of HIV infection is accompanied by a decrease in the volume of the caudate nucleus and white matter, as well as the cortical and subcortical gray matter of the brain [56–58], which is directly related to bipolar disorders [44]. Dysregulation in the metabolic activity of the basal ganglia was also identified. These phenomena were shown to be expressed in the form of hypermetabolism in the early stages of HIV infection and hypometabolism in the later stages of the infectious process [45].

It is believed that HIV-1 enters the CNS via the migration of virus-infected mononuclear blood cells/monocytes using the “Trojan horse mechanism”, which allows the virus to cross the blood–brain barrier (BBB) and infect the astrocytes, oligodendrocytes, and progenitor cells [46][47][48]. It has been shown that HIV-1 can change BBB permeability by modifying the expression of proteins involved in the maintenance of a dense barrier epithelium through the action of the viral tat protein [49][50]. Free viral particles can also penetrate the BBB via transcytosis, which is mediated by the viral protein gp120 [51] or by productive infection of the endothelial cells [52][53]. Some researchers believe that the freely circulating proteins gp120, tat, and nef can bind to the microvascular endothelial cells and cause changes in the BBB without direct involvement of the virus [54]. However, the main targets of HIV-1 invasion are the macrophages and microglia cells upon whose surfaces the co-receptors CXCR4 and CCR5 are expressed, which are necessary for the virus to enter cells [55][56][57] and which become cellular reservoirs for the long-term persistence of the virus in the CNS, thus playing an important role in the development of HIV-induced dementia [47][58][59]. The cerebrospinal fluid can also serve as a reservoir for the virus, which was confirmed by the results of the studies showing a high level of HIV-1 RNA in the cerebrosinal fluid of AIDS patients [60][61].

By penetrating into the CNS, HIV-1 induces an increase in the expression of chemokine receptors, the production of inflammatory mediators, the production of enzymes that destroy the extracellular matrix, and excitotoxicity mediated by glutamate receptors, which, in turn, initiates the activation of numerous downstream signaling pathways and disrupts neuronal and glial functions [47][62].

It has been shown that the viral protein tat can cause activation of the effector pyrine domain of the Nod-like receptor (NLR) containing the NLRP3 of the inflammasome in microglia, which leads to an increase in the levels of caspase-1 and IL-1β; this, in turn, induces the production of TNF-α and IL-6, thereby enhancing inflammatory processes [63]. In addition, HIV-1 infection of the microglial cells and macrophages induces the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which disrupts the functions of the signaling pathways associated with apoptosis and leads to cell cycle arrest, causing serious DNA damage and protein damage [64][65].

In astrocytes, in contrast to microglia and macrophages, the full replication of HIV-1 is limited [66][67]. These cells cannot produce full-fledged viral particles, but, at the same time, they contribute to the damage of brain cells by generating astrogliosis [68]. Virus-infected astrocytes can produce a number of viral regulatory proteins, such as tat, nef, and rev, which are involved in the development of inflammation and, therefore, neuronal damage [69]. It is known that tat activates HIV-1 transcription and enhances the process of the infection of primary astrocytes [70]. On the other hand, nef can induce the production of ROS by astrocytes, which leads to the rapid death of neurons, thereby causing the development of HIV-1-associated neurocognitive disorders and explaining the reason for the rapid development of dementia in patients not receiving ART or with low adherence to treatment [71].

Despite the fact that some oligodendrocytes express the CXCR4 co-receptor (one of the key receptors involved in the infection of HIV-1 cells) [72], it is believed that the most profound damage to oligodendrocytes is caused by the release of viral proteins from other cells infected with the virus [73]. It has been found that the viral tat protein promotes the death of oligodendrocytes or leads to their incomplete maturation, as well as the dysregulation of myelin protein expression, which reduces the ability of oligodendrocytes to create myelin sheaths [74][75]. Tat-induced damage to oligodendrocytes is associated with a change in the balance between the protein kinase CaMKIIβ and tyrosine kinase 3β (Gsk3β), leading to oligodendrocyte apoptosis and the development of a neuropathology [75].

Neurons cannot be infected with HIV-1, because they do not express the virus-specific receptors necessary for the virus to enter these cells. However, the viral proteins tat, nef, and gp120, which have high neurotoxic potential, can disrupt interneuronal connections and even cause neuronal death [76]. The tat protein interacting with the markers of the phagosomes in neurons changes the morphology of these formations, thereby preventing their fusion with lysosomes [77]. The nef protein has a similar effect, disrupting the autophagy process and causing neurodegenerative disorders [78].

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  83. Pu, H.; Tian, J.; Flora, G.; Lee, Y.W.; Nath, A.; Hennig, B.; Toborek, M. HIV-1 Tat protein upregulates inflammatory media-tors and induces monocyte invasion into the brain. Mol. Cell Neurosci. 2003, 24, 224–237, doi:10.1016/S1044-7431(03)00171-4.
  84. Bencheikh, M.; Bentsman, G.; Sarkissian, N.; Canki, M.; Volsky, D.J. Replication of different clones of human immunodefi-ciency virus type 1 in primary fetal human astrocytes: Enhancement of viral gene expression by Nef. J. Neurovirol. 1999, 5, 115–124, doi:10.3109/13550289909021993.
  85. Calcagno, A.; Atzori, C.; Romito, A.; Vai, D.; Audagnotto, S.; Stella, M.L.; Montrucchio, C.; Imperiale. D.; Di Perri, G.; Bono-ra, S. Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive pa-tients. J. Neurovirol. 2016, 22, 88–92, doi:10.1007/s13365-015-0371-x.
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  87. Hauser, K.F.; Hahn, Y.K.; Adjan, V.V.; Zou, S.; Buch, S.K.; Nath, A.; Bruce-Keller, A.J.; Knapp, P.E. HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology. Glia 2009, 57, 194–206, doi:10.1002/glia.20746.
  88. Zou, S.; Fuss, B.; Fitting, S.; Hahn, Y.K.; Hauser, K.F.; Knapp, P.E. Oligodendrocytes are targets of HIV-1 Tat: NMDA and AMPA receptor-mediated effects on survival and development. J. Neurosci. 2015, 35, 11384–11398, doi:10.1523/JNEUROSCI.4740-14.2015.
  89. Zou, S.; Balinang, J.M.; Paris, J.J.; Hauser, K.F.; Fuss, B.; Knapp, P.E. Effects of HIV-1 Tat on oligodendrocyte viability are mediated by CaMKIIbeta-GSK3beta interactions. J. Neurochem. 2019, 149, 98–110, doi:10.1111/jnc.14668.
  90. Nath, A.; Hauser, K.F.; Wojna, E.F.; Booze, R.M.; Maragos, W.; Predengarst, M.; Cass, W.; Turchan, J.T. Molecular Basis for Interactions of HIV and Drugs of Abuse. J. Acquir. Immune Defic. Syndr. 2002, 31, S62–S69, doi:10.1097/00126334-200210012-00006.
  91. Fields, J.; Dumaop, W.; Eleuteri, S.; Campos, S.; Serger, E.; Trejo, M.; Kosberg, K.; Adame, A.; Spencer, B.; Rockenstein, E.; et al. HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: Implications for HIV-associated neurocognitive disorders. J. Neurosci. 2015, 35, 1921–1938, doi:10.1523/JNEUROSCI.3207-14.2015.
  92. Kyei, G.B.; Dinkins, C.; Davis, A.S.; Roberts, E.; Singh, S.B.; Dong, C.; Wu, L.; Kominami, E.; Ueno, T.; Yamamoto, A.; et al. Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J. Cell Biol. 2009, 186, 255–268, doi:10.1083/jcb.200903070.
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