The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity

As successfully treated individuals with Human Immunodeficiency Virus (HIV)-infected age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorders (AUD) and Hepatitis C virus (HCV) infection. In 2013, people over 55 years old accounted for 26% of the estimated number of people living with HIV (~1.2 million). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection and comorbid risk factors, can lead to additive or synergistic effects on cognitive and motor function. This paper reviews the literature on neuropsychological and in vivo Magnetic Resonance Imaging (MRI) evaluation of the aging HIV brain, while also considering the effects of comorbidity for AUD and HCV.


INTRODUCTION
The concept and benefits of combining multiple drugs for treatment of Human Immunodeficiency Virus (HIV) infection was introduced in 1996 ( Gulick et al., 1997;Hammer et al., 1997). Polydrug therapies, referred to as highly active Antiretroviral Therapy (HAART) or equivalently, combination Antiretroviral Therapy (cART) were quickly incorporated into clinical practice, resulting in significantly reduced rates of hospitalizations, Acquired Immune Deficiency Syndrome (AIDS), and death (Moore and Chaisson, 1999). Because highly effective, combination regimens have since been the default in ART, and because newer one-pill options make use of the word "combination" obsolete, there has been a recent trend in referring to HIV treatments as ART instead of HAART or cART (Myhre and Sifris, 2017). Despite the effectiveness of ART in reducing HIV viral load and improving immune function, HIV infection continues to have major untoward public health and clinical consequences (Powderly, 2002).
Each year in the United States (US), 55,000-60,000 new infections are reported, with an estimated total of ∼1.2 million infected individuals. In 2013, people ≥50 years old accounted for 17-26% (or up to 312,000 individuals) of the HIV population (Center for Disease Control and Prevention, 2013). Older individuals are more likely to be diagnosed later in the course of the disease; indeed, 40% of people ≥55 are diagnosed with AIDS at the time of HIV diagnosis (Lindau et al., 2007;Brooks et al., 2012;Center for Disease Control andPrevention, 2015, 2016a,b). As individuals infected with HIV live longer (e.g., Thompson and Jahanshad, 2015), they are likely to accrue central nervous system (CNS) risk from factors such as substance use disorders (e.g., alcoholism), comorbid infections [e.g., hepatitis C virurs (HCV)], and medical conditions associated with ART treatment (Woods et al., 2004).
The considerable comorbidity of HIV infection and alcoholism (Cook et al., 2001;Miguez et al., 2003;Samet et al., 2004Samet et al., , 2007Conigliaro et al., 2006;Fuller et al., 2009;Bonacini, 2011) poses a greater public health burden than either condition alone. Individuals who drink heavily or have been diagnosed with DSM-IV alcohol abuse/dependence or DSM5 alcohol use disorder (AUD) are more likely to engage in risky sexual behaviors, delay testing for HIV, and postpone treatment (Fritz et al., 2010;Howe et al., 2011). Conversely, AUD may make it difficult for infected patients to follow the complex medication regimen prescribed to treat HIV or interfere with basic mechanisms of pharmacological treatment. HCV infects ∼25% of HIV-infected people in the US (Center for Disease Control and Prevention, 2011). HIV patients co-infected with HCV, who are also likely to drink heavily (>50 g alcohol/day), have higher mortality rates than low or moderate drinkers (Bonacini, 2011).
Cross-sectional studies have been instrumental in identifying brain regions and systems affected in HIV infection, but are limited to speculation about the potential interaction of these effects with aging and variables that change with disease progression or mitigation (e.g., Ances et al., 2012). Inconsistency in findings may be, at least in part, attributable to the cross-sectional examination of a dynamic disease. Indeed, any conclusion determining whether aging interacts and exacerbates the untoward effects of HIV infection, or alternatively, whether disease progression is a greater contributor than age to decline requires longitudinal study of the relevant variables in HIVinfected groups (e.g., Holt et al., 2012;Spudich and Ances, 2012).
In longitudinal modeling of the interactions of aging and HIV, two potential trajectories are often considered: premature (additive) or accelerated (synergistic) aging. Infection may facilitate processes compromised by older age resulting in premature aging, during which changes occur earlier but in parallel to normal aging or accelerated aging, wherein changes occur at a faster rate than in normal aging (Figure 1). Results may also depend on the metric evaluated (e.g., neuropsychological performance vs. brain volumes).
In the following, the literature on brain structure and function in HIV and relevant comorbidities (i.e., AUD, HCV) is reviewed, with a focus on longitudinal studies to help clarify the independent or interactive effects of older age. Table 1 provides a list of references used herein, concentrating on manuscripts published after 2007, for HIV and each comorbid condition, also indicating cross-sectional or longitudinal studies. Table 2 summarizes key findings highlighted in this review.

MEDICAL AND PSYCHIATRIC EFFECTS OF HIV AND COMORBIDITIES
Age-related medical conditions (e.g., diabetes, hypertension, coronary artery disease, stroke, Alzheimer's disease) are not usually observed in the general population until over age 60: in HIV-infected patients, such conditions may present at middle age or sooner (Guaraldi et al., 2014). HIV-infection is also associated with frailty, the likelihood of which increases with age (Desquilbet et al., 2007). Accelerated aging in HIV may FIGURE 1 | Longitudinal modeling of the interactions of aging and HIV consider two potential trajectories: premature and accelerated aging. Infection may facilitate processes associated with aging resulting in premature aging, during which changes occur earlier but in parallel to normal aging or accelerated aging, wherein changes occur at a faster rate than in normal aging.
Because healthy aging results in global increases in immune activation and immune senescence (Schuitemaker et al., 2012), it is thought that a canonically dysregulated immune system (e.g., altered T cell production) can hasten medical or psychiatric disease (Önen and Overton, 2011), thereby contributing to premature or accelerated aging in HIV (Watkins and Treisman, 2012;Zapata and Shaw, 2014).
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Frontiers in Aging Neuroscience | www.frontiersin.org HCV liver damage progresses more rapidly in HIV and may accelerate the course and impair the management of HIV (Luetkemeyer et al., 2006;Weber et al., 2006;Chamie et al., 2007;Kim and Chung, 2009;Soriano et al., 2010). In addition, individuals seropositive for HCV have co-occurring insulin resistance beyond what might be predicted by chance (Harrison, 2008). HCV patients frequently report fatigue, lassitude, depression, and poor quality of life (Hilsabeck et al., 2003;Adinolfi et al., 2015). Emerging evidence supports an additive role of HCV and HIV on depression (Ramasubbu et al., 2012), which can negatively impact medical outcomes (Šprah et al., 2017).
Indeed, toxicity of ART goes beyond originally reported side effects of medications. An unexpected relationship between high current CD4 and deterioration of clinical status is an active area of investigation (e.g., Jernigan et al., 2011;Nasi et al., 2017) and a growing concern for the aging HIV population (Manji et al., 2013;Zaffiri et al., 2013). This condition, referred to immune reconstitution inflammatory syndrome (IRIS), applies to HIV patients who experience worsening symptoms as a result of anti-retroviral therapy mediated immune restoration (Venkataramana et al., 2006;Johnson and Nath, 2010). The effects of IRIS on brain structure may not be visible with conventional MRI (Narvid et al., 2016), but may be detectable with quantitative diffusion tensor imaging (DTI) (Zhu et al., 2013), which focuses on the integrity of white matter microstructure.
To account for variability seen in neuropsychological performance in cross-sectional studies (Schretlen et al., 2003), it has been posited that an increase over time (6-month interval) in intra-individual variability (or dispersion) in neurocognitive performance contributes to poorer antiretroviral medication adherence, which in turn can lead to additional neurocognitive impairments, precipitating a deteriorating cycle (Thaler et al., 2015). The Multicenter AIDS Cohort Study (MACS) enrolled a total of 6972 men from sites in Baltimore, Washington, Chicago, Los Angeles, and Pittsburgh at three separate time points: in 1984-1985, 1987-1991, and 2001-2003. Neuropsychological evaluation included measures from multiple domains. A datadriven Mixed Membership Trajectory Model technique was used to investigate potential trajectories of cognitive impairment. The findings suggest three distinct trajectories: "normal aging" was defined as a low probability of mild impairment until age 60; "premature aging" was defined as mild impairment starting at age 45-50 (i.e., "premature aging" relative to "normal aging" was offset to the left by 25+ years); "unhealthy aging" was defined as mild impairment at ages 20-39. Clinically defined AIDS, HCVinfection, depression, and race affected an individual's trajectory classification (Molsberry et al., 2015). Our work comports with the results of the MAPS study showing that cognitive performance slope differences between control and HIV groups can be modeled as premature aging, in that differences between the patients and the controls occur without interactions with aging .
Studies focused on neuropsychological performance in AUD show impairments in memory, psychomotor speed, and executive functioning: problems in visuospatial and emotional regulation domains appear to be unique to AUD (Chanraud et al., 2007;Fama et al., 2009;Oscar-Berman et al., 2014;Wilcox et al., 2014;Le Berre et al., 2017). Motor effects of AUD include compromise of upper limb motor abilities, and gait and balance (Sullivan et al., 2000b(Sullivan et al., ,c, 2002Vassar and Rose, 2014). Peripheral neuropathy reported in AUD has been related to nutritional deficiencies (Chopra and Tiwari, 2012;Noble and Weimer, 2014).
Substance abuse can independently contribute to neuropsychological impairments in HIV (e.g., Gomez et al., 2017). In a recent study, 52% of HIV positive patients showed cognitive deficits, often related to high alcohol consumption (McNamara et al., 2017). In studies aimed at discerning the independent effects of HIV and AUD (e.g., Fama et al., 2012), impairments in planning and free recall of visuospatial material marked AUD, whereas impairments in psychomotor speed, sequencing, narrative free recall, and pattern recognition marked HIV. Our work demonstrates that tests of executive function, episodic memory, and processing efficiency (expressed as ageand education-corrected composite Z-scores) show a graded effect, with HIV+AUD performing worse than controls on executive function and episodic memory and worse than AUD alone or HIV alone on episodic memory (Fama et al., 2016): in HIV+AUD, age was a unique predictor of poor episodic memory (Figure 2). Our work comports with the literature that comorbidity for HIV+AUD results in compounding effects (Rothlind et al., 2005;Fama et al., 2014) on declarative memory (Fama et al., , 2016, remote memory (Fama et al., 2011), selective attention and conflict processing (Schulte et al., 2005), psychomotor speed , gait and balance , and quality of life .
In summary, available evidence suggests that neurocognitive performance in ART-treated HIV individuals shows premature aging. HIV, AUD, and HCV can independently impair neuropsychological functioning and appear to have additive effects on some domains of cognition, which in practice can have significant effects on key outcomes such as employment status (van Gorp et al., 1999;Heaton et al., 2004), medication adherence (Hinkin et al., 2004), and driving safety (Marcotte et al., 2006).

Macrostructural Magnetic Resonance Imaging (MRI)
In the ART era, clinical MRI scanning reveals relatively few gross intracranial abnormalities in HIV, particularly when neurological signs are absent (Nishijima et al., 2014). Although severe brain atrophy is uncommon in HIV stabilized by treatment, brain volume deficits can be detected with quantitative methods in select regions of the cortex, basal ganglia, and cerebellum (Aylward et al., 1993;Di Sclafani et al., 1997;Stout et al., 1998;Tagliati et al., 1998;Ragin et al., 2012;Kallianpur et al., 2013;Underwood et al., 2017a). Cortical areas with gray matter volume deficits in HIV with viral suppression, relative to healthy controls, include frontal, cingulate, sensorimotor, and parietal regions (Heaps et al., 2012;Li et al., 2014;Pfefferbaum et al., 2014;Clark et al., 2015;Janssen et al., 2015;Wang et al., 2016). Those without complete viral suppression exhibit greater volume deficits than virally-suppressed individuals (Cardenas et al., 2009;Kallianpur et al., 2013;Hines et al., 2016). The imaging literature typically reports the effects of HIV on gray matter volume [see the following for exceptions] (Corrêa et al., 2016a;du Plessis et al., 2016;Castillo et al., 2017). In studies that assessed cortical thickness rather than cortical volume, HIV effects can be evident in areas such as the insula and temporal cortices Sanford et al., 2017).
Subcortical regions with significantly smaller volumes, particularly in older HIV subjects relative to healthy controls, include thalamus, hippocampus, caudate, putamen, and pallidum (Dewey et al., 2010;Li et al., 2013;Wade et al., 2015;du Plessis et al., 2016;Wright et al., 2016;Sanford et al., 2017). Brain tissue abnormalities have been reported to correlate with nadir CD4 cell counts (Thompson et al., 2005;Jernigan et al., 2011;Kallianpur et al., 2012;Hua et al., 2013). However, HIV individuals with an active life style (energy use above resting expenditure) were found to have a larger putamen (Ortega et al., 2015), and longitudinal study reveals that increasing CD4 counts (notwithstanding IRIS) are associated with increases in subcortical gray matter volumes (Fennema-Notestine et al., 2013) and slower tissue volume declines .
As described for compromised neuropsychological performance in HIV, brain volume deficits in the ART era may be associated with more traditional risk factors (e.g., age, education, diabetes) than with HIV-related variables (Bonnet et al., 2013;Lake et al., 2017; but see Ragin et al., 2011;Kallianpur et al., 2016). Although HIV and aging appear to contribute independently to heighten brain structural vulnerability (Ances et al., 2012), HIV may accelerate brain aging (Cysique et al., 2013;Cole et al., 2017). Consequently, despite persistent control of plasma viremia, older HIV infected patients demonstrate more rapid progressive brain compromise when compared to healthy aging (Clifford et al., 2017).
The few published longitudinal volumetric MRI studies have been conducted over relatively brief intervals, typically 1-2 years. An initial study found faster rate of cortical volume decline in mild (CDC stage A) and severe (CDC stage C) stages of HIV infection relative to changes observed in infection-free controls and faster rates of white matter volume decline in the HIV-infected subgroup with stage C than stage A severity level. Further, decline in caudate nucleus volume and increase in ventricular volume were greater in the HIV-infected group that progressed from a less severe to a more severe CDC stage across MRI sessions, and these changes in brain volumes correlated with decline in CD4 cell count (Stout et al., 1998). A 2-year longitudinal study indicated widespread white matter volume loss and posterior gray matter loss (parietal, occipital, and cerebellar) in virally-suppressed HIV individuals, depending on analysis approach; those without complete viral suppression exhibited accelerated volume loss in gray and white matter compared with declines measured in controls (Cardenas et al., 2009). Examination of HIV infected individuals before and about 6 months after starting ART revealed improvement in neuropsychological test performance but no appreciable change in regional brain volumes (Ances et al., 2012). In this relatively small study, older age and HIV infection were independently related to smaller volumes of the caudate, with evidence for premature aging of the caudate in HIV-infected participants, while volumes of the amygdala and corpus callosum were sensitive to HIV but not aging.
We evaluated brains of 51 HIV and 65 controls from 351 longitudinal MRI scans and concurrent neuropsychological evaluation collected 2 or more times over 6 months to 8 years . Although HIV individuals were in good general health and free of clinically detectable dementia, significant volume effects, where HIV-infected participants had greater volumes in CSF regions and smaller volumes in tissue regions than controls, were found in the Sylvian fissures, cingulum, insula, thalamus, and hippocampus. Significant slope effects, where the HIV-infected group showed greater change per year over the years of observation than the control group, were detected in the lateral ventricles, insula, and hippocampus. Greater acceleration in slope with advancing age in the HIVinfected individuals was found for frontal, temporal, and parietal cortices and thalamus (Figure 3). In this study, the most consistent and robust predictors of brain volume trajectories were CD4 count and duration of HIV infection .
In non-cirrhotic HCV patients relative to controls, a recent study suggests that cortical thickness is reduced in frontal and occipital cortices (Hjerrild et al., 2016; also see Iwasa et al., 2012). HIV + HCV co-infection has been associated with increased incidence of neurovascular disease (Jernigan et al., 2011;Ojaimi et al., 2014; but see Ramos-Casals et al., 2007) and compromised brain perfusion (Bladowska et al., 2014), but the effects of HIV and HCV co-infection on brain macrostructural integrity is an area for further investigation. In summary, structural imaging suggests that HIV infection may lead to accelerated aging of the brain, which is compounded by AUD comorbidity, particularly in subcortical regions such as the thalamus. Additional work is required to determine whether non-cirrhotic HCV is associated with regional brain volume deficits and whether HIV+HCV coinfection has additive effects on reducing regional brain volumes.

White Matter Hyperintensities
White matter damage can be measured by examining white matter hyperintensities (WMH) on fluid attenuated inversion recovery (FLAIR) images from MRI. WMH may reflect vascular or inflammatory brain changes (Maniega et al., 2015;Shoamanesh et al., 2015). The prevalence of cerebrovascular events in HIV remains higher, in relatively younger patients, despite treatment, than in the general population (Haddow et al., 2014;Arentzen et al., 2015). The frequency of cerebrovascular disease increases with age (Kendall et al., 2014) and HIV individuals with cerebrovascular disease are more likely to have cognitive deficits (Foley et al., 2008;Nakamoto et al., 2012).
WMH are a frequent finding on brain MRI of elderly subjects (over aged 60) and associated with hypertension (e.g., Rostrup et al., 2012;Peng et al., 2014). A number of studies report a greater prevalence of WMH in HIV relative to healthy controls (Foley et al., 2008;Su et al., 2016), specifically affecting frontal lobes (McMurtray et al., 2008). While one study reports that with older age, patients with HIV have a greater number of WMH relative to age-matched healthy controls related to a history of AIDS, current CD4, and active HCV infection (Seider et al., 2016), another found a similar number of WMH volumes in HIV and controls (Watson et al., 2017), explained by hypertension (Su et al., 2016;Watson et al., 2017).
There is little evidence that alcohol consumption increases WMH load (e.g., Anstey et al., 2006). In non-cirrhotic HCV patients relative to controls, imaging provides evidence for an increased incidence of WMH representing cerebral vasculitis (Heckmann et al., 1999;Casato et al., 2005;Bezerra et al., 2011). Indeed, in HIV, the presence of HCV was the strongest predictor of WMH (Robinson-Papp et al., 2017).

Structure/Function Relationships
A primary goal of evaluating structure/function relationships in HIV is to advance understanding of the neural substrates of HIV-associated motor and cognitive compromise. Significant, but non-specific correlations have been reported between the severity of global brain atrophy and general cognitive  Heaps et al., 2015). By contrast, cortical thinning of the retrosplenial cortex has been proposed as a selective contributor to general cognitive impairment in HIV (Shin et al., 2017). A number of studies report deficits in regional brain volumes associated with poor cognitive performance in HIV: the caudate with psychomotor performance (Kieburtz et al., 1996;Paul et al., 2002;Kallianpur et al., 2016); the anterior cingulate with emotion processing (Clark et al., 2015); the prefrontal cortex with verbal learning and memory (Rubin et al., 2016). The assortment of brain regions implicated likely reflects heterogeneity in disease course. Indeed, post-ART, global, cortical-driven pathogenesis rather than subcortical dysfunction is a more likely contributor the varying HIV clinical manifestations (Foley et al., 2008). Cognitive heterogeneity post-ART thus requires further evaluation of select brain structure/function relationships, particularly in stably-treated, aging HIV cohorts, with comorbid risk factors.
In HIV-infected alcoholics, smaller thalamic volumes were associated with poorer performance on tests of explicit (immediate and delayed) and implicit (visuomotor procedural) memory (Fama et al., 2014), again indicating the thalamus as a structure that is particularly susceptible to HIV and the compounding effects of AUD. The potential for segmentation of thalamic subregions (Behrens et al., 2003;Deoni et al., 2007;Zhang et al., 2010;Deistung et al., 2013;Kim et al., 2013;Barron et al., 2014) holds promise for a more refined understanding of brain structure/function relationships and affected neural circuitry (Fama et al., 2016) in HIV.

Magnetic Resonance Spectroscopy (MRS)
MRS is a modality used to quantify brain metabolites, typically N-acetyl aspartate (NAA), choline-containing compounds (Cho), and total creatine (tCr). NAA is an indicator of neuronal integrity, with decreases suggesting neuronal dysfunction (e.g., Zahr et al., 2010Zahr et al., , 2013. The signal from Cho, including contributions from free choline, glycerophosphorylcholine, and phosphorylcholine (Miller, 1991), is a marker for cell membrane synthesis and turnover. The signal from tCr, with contributions from creatine and phosphocreatine, represents the high-energy biochemical reserves of neurons and glia (Inglese et al., 2003). Less frequently reported, as their quantification is more challenging, are levels of myo-Inositol (mI) and glutamate (Glu). Because mI, an osmolyte, is primarily present in glial cells (Brand et al., 1993), it is considered a glial marker. Glu is a ubiquitous molecule used in cellular metabolism and is the principal excitatory neurotransmitter (Thangnipon et al., 1983;Fonnum, 1984).
During acute/early infection and at two follow-up time points (2 and 6 months), greater numbers of activated (CD16+) monocytes were associated with lower NAA and higher Cho levels in frontal cortex (Lentz et al., 2011). Similarly, above control levels of Cho were identified in basal ganglia in acute HIV; these resolved to control levels at 6 month following initiation of ART . Similar findings (longitudinal increases in Cho) were reported in frontal white matter and parietal gray matter prior to ART initiation, with resolution following ART (Young et al., 2014). By contrast, a study in chronic HIV with longer intervals between MRS showed that despite stable ART and virological suppression, and in both asymptomatic and cognitively impaired subgroups, HIV-infected subjects showed significant annual decreases in brain metabolites (including NAA, Cho, tCr, and Glx) in midfrontal cortex, frontal white matter, and basal ganglia (Gongvatana et al., 2013).
In a previously published work, we challenged the specificity of Cho and mI as markers of neuroinflammation. Significant group effects were evident for striatal Cho and striatal mI, higher in HIV+AUD than in controls (Figure 4). Correlations evaluated in HIV groups only (i.e., HIV, HIV+AUD) demonstrated that having HCV or an AIDS-defining event was associated with higher Cho; lower Cho levels, however, were associated with low thiamine levels and with ART. Higher levels of mI were related to greater lifetime alcohol consumed, whereas ART was associated with lower mI levels (Zahr et al., 2014). These results demonstrate that competing mechanisms can influence Cho and mI levels, and that elevations in these metabolites cannot necessarily be interpreted as reflecting a single underlying mechanism such as neuroinflammation.

Microstructural Diffusion Tensor Imaging (DTI)
Examination of brain microstructural integrity using DTI has detected subtle HIV-related differences from controls [e.g., low fractional anisotropy (FA) and high mean diffusivity (MD)] in markers of myelin (radial or transverse diffusivity) and axonal (axial or longitudinal) integrity, even in normal-appearing white matter, notably in corpus callosum and frontal lobe white matter (e.g., Pfefferbaum et al., 2007Pfefferbaum et al., , 2009aChen et al., 2009;Hoare et al., 2011;Towgood et al., 2011;Du et al., 2012). Variable results from DTI studies may be due, at least in part, to timing of evaluation relative to treatment (i.e., treatment naïve, currently un-medicated, chronically medicated, or older HIV infected individuals). For example, in early, treatment naïve HIV infection, white matter impairment (Tang et al., 2017) correlated with days since infection (Wright et al., 2015). In those on ART, a number of fiber tracts, including those of the corpus callosum and corona radiate are often reported as compromised (Leite et al., 2013;Xuan et al., 2013;Su et al., 2016;Wang et al., 2016). Effects on DTI metrics may also depend on presence of neurological complications (Corrêa et al., 2015), with symptomatic individuals showing effects extending to frontal areas (Zhu et al., 2013). Chronic relative to initial infection often shows more substantial differences in DTI metrics related to biomarkers of infection (e.g., viral load and immune compromise), disease duration, and ART duration (Wright et al., 2015;Cordero et al., 2017;Strain et al., 2017), which complicates attempts to distinguish effects of age, as age is often correlated with the duration of infection and ART.
Most DTI studies report independent effects of age and HIV on DTI metrics, but no evidence for an interaction (Gongvatana et al., 2011;Towgood et al., 2011), even in subjects over the age of 60 (Nir et al., 2014). Instead, for example, longer HIV duration may interact with the presence of the apolipoprotein E4 allele (which increases the risk for Alzheimer's disease) Wendelken et al., 2016) or impaired glucose metabolism (Nakamoto et al., 2012) to compromise the brain in older HIV-infected individuals. A single study reported significant age by HIV interactions for decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ relative to seronegative control participants (Seider et al., 2016); HIV duration as measured by time since diagnosis was not a significant predictor of white matter damage in the described cohort suggesting that the reported interaction truly reflected the effects of aging. Support for an interactive effect of aging and HIV on DTI metrics comes from a longitudinal DTI study suggesting greater than normal age-related changes on the genu of HIV patients at 1 year follow up (Chang et al., 2008). A more recent longitudinal study, with an approximate 2-year follow-up interval, did not show differences in metrics between the first and second evaluation (Corrêa et al., Zahr Aging With HIV + Comorbidities 2016b), possibly because viremia was better controlled in the later study.
Quantitative analysis DTI data from cross-sectional study of 4-groups (controls, AUD, HIV, HIV+AUD) revealed in all patient groups relative to controls lower integrity of callosal regions  and uncinate fasciculus (Schulte et al., 2012): degradation of callosal microstructure showed evidence for compounded AUD+HIV effects .

SUMMARY AND CONCLUSIONS
Getting old with HIV appears to cause premature aging with respect to medical conditions, psychiatric comorbidities, and neurocognitive performance. Structural MRI findings suggest accelerated aging of select brain gray matter volumes, but equivocal evidence for an interactive increase in WMH burden in older HIV-infected individuals. Current DTI studies are similarly conflicting as to whether older age and HIV have interactive effects on white matter integrity. The literature remains sparse with respect to longitudinal studies, which will help distinguish between healthy, premature, and accelerated aging with HIV.
ART has largely controlled the HIV epidemic, but fundamental questions regarding the precise cause of neurocognitive dysfunction in HIV remain. In the post-ART era, persistent issues related to an aging HIV population include effects of common comorbid conditions, such as AUD and HCV infection. Neuroimaging points to the sensitivity of the thalamus to HIV infection. High-resolution imaging and segmentation of thalamic substructures may provide a more refined understanding of the substrates underlying cognitive decline in HIV. DTI has been underutilized in studying the HIV brain and thus also holds promise for clarifying the brain regions involved in HIV-associated cognitive and motor impairments and in explicating mechanisms that may contribute to dysfunction with age. Free water imaging, a DTI analysis method that improves the specificity and sensitivity of DTI by accounting for extracellular water (Pasternak et al., 2009Metzler-Baddeley et al., 2012), may permit a better understanding of neuroinflammatory processes in HIV (Strain et al., 2017) and aging. A better understanding of the aging HIV brain will help in the development of integrated healthcare approaches for these complicated patients.

AUTHOR CONTRIBUTIONS
NMZ envisioned and wrote this review manuscript and is accountable for all aspects of the work.

FUNDING
This study was supported with grant funding from the National Institute of Alcohol Abuse and Alcoholism (NIAAA): AA017347, AA017168, and AA013521.

ACKNOWLEDGMENTS
NMZ would like to acknowledge Drs. Adolf Pfefferbaum and Edith V. Sullivan for supporting this work and reviewing in-progress versions of the manuscript.