**2. Neuropsychological changes**

#### **2.1. Depression: serotonin loss**

With normal aging, the brain suffers from serotonin (5-HT) neuron and neurotransmitter loss. This deficit in serotonergic neurotransmission might promote the occurrence of depression in the elderly population [42]. The incidence of major depression is estimated from 1 to 10% in a population older than 60 years of age, while depressive symptoms may affect up to 20% [43, 44]. Even if it is not considered as a normal aging event, the loss of serotonin and subsequent depression is a common even among the elderly.

Depression is significant comorbidity with a prevalence superior to 30% in some studies in HIV-infected patients [45, 46]. Among a cohort of 13,874 HIV-infected patients, 44% percent of the study population had depression, and 15% of the whole cohort was prescribed SSRIs [47].

The essential amino acid l-tryptophan (Trp) is the precursor of some essential metabolites produced during the course of its degradation, along with different pathways, like the kynurenine (KYN) pathway and the serotonin, 5-hydroxytryptamine or 5-HT pathway. During the kynurenine pathway, the tryptophan is converted by the enzymes Tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase 1 (IDO1), IDO2. The resulting product is further degraded to kynurenine (KYN), which is a precursor of bioactive compounds, including quinolinic acid (QUIN), that subsequently activate or inhibit NMDA neurotransmission. Proinflammatory cytokines, including interferon-γ (IFN-γ), interleukin-1 β (IL-1β), and IL-6, can further induce IDO-1 and TDO and thus activate this pathway, reducing the availability of TRP for the serotonin synthesis pathway [48–51].

HIV-1 clade B Tat is responsible for the up-regulation of IDO and the down-regulation of 5-HT gene and protein expressions. Also, HIV-1 clade B Tat reduces 5-HT with a concomitant increase in KYN levels as compared to HIV-1 clade C Tat [52].

HIV+ subjects present a reduced breakdown of Phe to tyrosine (Tyr) [53, 54] and a faster conversion of trp to kynurenine (Kyn) [55], which is correlated with higher levels of immune activation markers like interferon-γ (IFN-γ) or neopterin in HIV-1 individuals [56]. Accelerated trp breakdown was correlated with neuropsychiatric symptoms in HIV patients [55, 57].

It is interesting to note that serotonin treatment decreases the HIV-I replication in human macrophages. Indeed 5-HT decreases the β-chemokine receptor, CCR5, and increases the CCL5 chemokine, MIP-1α, implying an effect of 5-HT on 5-HT1A receptors on macrophages [58]. Further, some studies show that in HIV+ individuals the blocking of the re-uptake of serotonin (SSRIs) is associated with the up-regulation of NK cells [59, 60]. Serotonergic pathways are important in the function of natural killer (NK) cells and CD8 + T cells [61].

#### **2.2. HIV-1 and risks of Alzheimer's disease (AD) pathogenesis**

of pyramidal neurons situated in the superior temporal, precentral, and prefrontal cortices in humans [8]. HIV-1 Tat expression in pyramidal CA1 neurons decrease the number of apical dendritic spines, without the evidence of pyramidal death but with the disruption of the distribution of the synaptic proteins gephyrin and synaptogtagmin2 [39]. The Tat expression induces synapto-dendritic modifications in the hippocampus that will disrupt the LTP in CA1

HIV-1 Tat protein injection into the hippocampus showed that Tat plays on extra-synaptic NMDA receptors but not on synaptic. Additionally, it suppresses long-term potentiation (LTP) followed by a diminution of spatial learning. Tat protein induces the phosphorylation of NMDA receptor subunits NR2A and NR2B in a tyrosine kinase-dependent manner, which triggers Ca2+ flux. Ca2+ entry through synaptic NMDA receptors activates cAMP response element binding protein (CREB) activity, and confers antiapoptotic ability, while Ca2+ entry through extrasynaptic NMDA receptors shuts off CREB pathway [40]. Some recent work shows that CREB protein holds an essential role in memory formation. CREB protein brings changes in global neuronal excitability. CREB overexpression results in more action potential for each pulse and a smaller after-hyperpolarization (AHP) after a chain of action potentials.

conductance. By enhancing neuronal excitability, CREB might increase the inclusion of

With normal aging, the brain suffers from serotonin (5-HT) neuron and neurotransmitter loss. This deficit in serotonergic neurotransmission might promote the occurrence of depression in the elderly population [42]. The incidence of major depression is estimated from 1 to 10% in a population older than 60 years of age, while depressive symptoms may affect up to 20% [43, 44]. Even if it is not considered as a normal aging event, the loss of serotonin and subsequent depres-

Depression is significant comorbidity with a prevalence superior to 30% in some studies in HIV-infected patients [45, 46]. Among a cohort of 13,874 HIV-infected patients, 44% percent of the study population had depression, and 15% of the whole cohort was prescribed SSRIs [47]. The essential amino acid l-tryptophan (Trp) is the precursor of some essential metabolites produced during the course of its degradation, along with different pathways, like the kynurenine (KYN) pathway and the serotonin, 5-hydroxytryptamine or 5-HT pathway. During the kynurenine pathway, the tryptophan is converted by the enzymes Tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase 1 (IDO1), IDO2. The resulting product is further degraded to kynurenine (KYN), which is a precursor of bioactive compounds, including quinolinic acid (QUIN), that subsequently activate or inhibit NMDA neurotransmission. Proinflammatory cytokines, including interferon-γ (IFN-γ), interleukin-1 β (IL-1β), and IL-6, can further induce IDO-1 and TDO and thus activate this pathway, reducing the availability of

channels, and CREB might be involved in variations in

pyramidal neurons and subsequently bring deficits in learning and memory.

AHP is usually engendered by K<sup>+</sup>

6 Advances in HIV and AIDS Control

neurons into the memory trace [41].

**2. Neuropsychological changes**

sion is a common even among the elderly.

TRP for the serotonin synthesis pathway [48–51].

**2.1. Depression: serotonin loss**

K<sup>+</sup>

Apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) play a role in cardiovascular disease and lipoprotein metabolism but are mainly studied for their contribution in neurodegeneration in Alzheimer's disease [62–64]. HIV-associated dementia (HAD) is a neurological condition with clinicopathological features similar to Alzheimer's disease [65].

Early research presented in Nature Medicine in 1998 measures the risk of dementia in patients who presented E4 isoform for apolipoprotein E (APOE). Compared to the normal subjects, they presented twice more dementia and peripheral neuropathy, concluding that a long-term infection brings an increased risk of dementia for E4(+) subjects [66], with an even bigger risk with low CD4+ cell count and length of infection. It is today widely accepted that the *APOE* ε4/ε4 genotype is associated with a faster disease course and progression to death compared with the *APOE* ε3/ε3 genotype. However, an association between the ε4/ε4 genotype and HIV-associated dementia (HAD) was not identified [67].

APOEε4 allele(s) may lead to premature aging with neurodegeneration in younger HIV patients preceding the development of HAND, potentially because of greater neuroinflammation or more abundant amyloid deposition in younger HIV subjects with APOEε4 allele(s) [4, 68]. Recent neuroimaging studies present conflicting results. One study on 237 patients shows that the ApoEε4 allele does not affect brain integrity, gray, or white matter, in their cohort of HIV+ individuals [69]. Another study on 76 patients shows brain atrophy, especially in the posterior corpus callosum, thalamus, and brainstem [70]. These individuals were older than 60, which could explain the discrepancy between the studies; the deleterious effects could be age dependent [71].

The APOEε4 genotype is a risk factor for elevated cholesterol in ART-adherent HIV(+) men aged >50 years [72] with a risk for a higher cognitive decline associated and cardiovascular problems.

All these studies taken together, it is now clear that individuals with HIV and the ApoE gene exhibited greater cognitive deficits when tested for attention, executive function, and working memory than HIV-infected individuals with ApoE4 genotype carriers.
