Cerebral Small Vessel Disease in HIV-1 Infected Individuals

Soontornniyomkij V*

Department of Psychiatry, University of California San Diego, USA

*Corresponding author: Soontornniyomkij V, Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-2623, USA

Received: August 12, 2014; Accepted: August 15, 2014; Published: August 19, 2014

Perspective

While HIV-associated dementia is rare in the current era of highly active antiretroviral therapy (HAART), the milder forms of HIV-associated neurocognitive disorders (HAND), asymptomatic neurocognitive impairment and mild neurocognitive disorder, are common [1,2]. Patients could develop HAND even when their systemic HIV infection and immune function remain under control [2-4]. Recent postmortem brain studies suggest that HAND is not necessarily associated with HIV encephalitis [5-7] and may be related to various comorbid factors such as long-term exposure to antiretroviral medications [8], age-related cerebrovascular and neurodegenerative changes [9,10], co-infection with hepatitis C virus, and substance use (e.g., methamphetamine) [11,12].

Previous studies suggest that HIV-infected individuals are at increased risk of ischemic cerebrovascular diseases, potentially caused by infective vasculitis, brain opportunistic diseases, hypercoagulopathy, cardiac embolism, or HIV infection itself [13- 20]. Included among a variety of brain vessel pathologies found in this context is cerebral small vessel disease (CSVD), known in histopathological terminology as arteriolosclerosis: concentric intramural hyalinization of small arteries or arterioles [15,17,19]. In the general population, CSVD is associated with diabetes, hypertension, and older age [21], although the underlying mechanisms are still unknown. In patients who receive HAART, particular antiretroviral drugs may directly cause injury to vessel walls or indirectly induce metabolic abnormalities (e.g., dyslipidemia and insulin resistance) that accelerate the development of atherosclerotic large vessel disease [22,23]. Nonetheless, the potential impact of HAART exposure on the development of ischemic cerebrovascular diseases, including CSVD, remains controversial [14,15,18,19,24-26]. In a communitybased study [27], the presence of punctate white matter lesions (hyperintensities) on magnetic resonance imaging (MRI) was found to be associated with older age and higher systolic blood pressure; furthermore, there was a trend toward the direct association between white matter lesions and HAART exposure. Whereas in the general population white matter lesions detected on MRI are thought to represent ischemic lesions caused by CSVD [28], the similar lesions in HIV-infected individuals may also reflect foci of HIV-associated or inflammatory white matter injury [29-32].

We propose that chronic toxic effects of antiretroviral drugs on the cell components of vessel walls can contribute to CSVD, which may be one of the key underpinnings of HAND. More severe forms of CSVD may lead to neurocognitive impairment via cerebral blood flow restriction sufficient to produce white matter lesions and microinfarcts. In mild CSVD, neurocognitive compromise may be associated with disturbance of cerebrovascular autoregulation and deficiency in functional hyperemia, which together could impair new protein synthesis in neurons required for synaptic plasticity and memory formation [21,33-36].

Recently, we have conducted a cross-sectional clinicopathological analysis using postmortem brain specimens obtained from the California NeuroAIDS Tissue Network and reported that exposure to protease inhibitor (PI)-based HAART might increase the risk of CSVD in the forebrain white matter [37]. Specifically, using multivariable logistic regression analyses we found direct associations between PI-based HAART exposure and higher likelihood of both mild and moderate/severe CSVD after statistically adjusting for diabetes. Moderate/severe CSVD was associated with diabetes after statistically adjusting for HAART exposure, older age (i.e., 50 years or older), and hypertension. Importantly, we found that mild CSVD was associated with HAND even after statistically adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age. While the mechanisms remain to be delineated, it is possible that particular drug components of PI-based HAART may be toxic to the cellular components of cerebral small vessels, such as vascular endothelial cells and smooth muscle cells, leading to vessel wall degeneration. It is also possible that some drugs in PI-based HAART contribute indirectly to CSVD by inducing metabolic abnormalities such as dyslipidemia and insulin resistance, as they have been implicated in the premature development of atherosclerotic large vessel disease [22, 23].

It is important to note that different antiretroviral drugs even in the same class may carry different degrees of toxicity on cerebral vessels. This matter can be addressed using experimental animals [38] and in vitro cell systems [39]. Also, the toxic effects of antiretroviral drugs may vary with the duration of drug use and the rate of drug metabolism in individual patients.

Vessel mineralization (defined histopathologically as intramural deposition of basophilic amorphous material in small and mediumsized arteries) found primarily in the globus pallidus was consistently reported in pre-HAART HIV autopsy cohorts [40,41]. In our recent study [37], in contrast to CSVD, there was no significant association between vessel mineralization and HAART exposure. In addition, the presence of vessel mineralization was not significantly associated with that of CSVD. These findings suggest that vessel mineralization may be pathophysiologically different from CSVD and mediated by the HIV-related effects on vessel walls in a brain region-specific manner.

While the pathophysiology of atherosclerotic large vessel disease has been studied extensively with regard to the roles of inflammation and vascular cell proliferation [42-44], the underlying mechanisms of arteriolosclerosis are largely unexplored other than the identification of associated risk factors (i.e., diabetes, hypertension, older age) [21]. For future research directions, it is of interest to investigate the molecular mechanisms of drug toxicity (e.g., antiretroviral drugs,methamphetamine) to the cell components of cerebral vessels, protective effects of potential rescue agents (e.g., antioxidants, phytoestrogens), and identification of potential biomarkers for CSVD in body fluids or more accessible peripheral tissues. For instance, specific antiretroviral drugs or drug combinations may affect the integrity and function of cerebral vessels by inducing premature senescence of vascular endothelium and smooth muscle cells [39,45]. The ritonavir-lopinavir PI combination could induce premature aging of endothelial cells by mechanisms involving oxidative stress and dysregulation in the maturing process of lamin-A (an intermediate filament protein constituting the structural scaffold for the nuclear lamina) [39].

Cerebral Small Vessel Disease in HIV-1 Infected Individuals

Perspective

References