Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) is a common condition in both developed and developing nations, but its cause is largely unknown. Previous research has inconsistently linked Alzheimer's disease (AD), viral burden, and inflammation to the onset of HAND in HIV-infected individuals. Here we simultaneously measured cerebrospinal fluid (CSF) levels of established amyloid and tau biomarkers for AD, viral copy numbers, and six key cytokines in 41 HIV-infected individuals off combination anti-retroviral therapy (14 with HAND) who underwent detailed clinical and neuropsychological characterization, and compared their CSF patterns with those from young healthy subjects, older healthy subjects with normal cognition, and older people with AD. HAND was associated with the lowest CSF levels of phosphorylated tau (p-Tau181) after accounting for age and race. We also found very high CSF levels of the pro-inflammatory interferon gamma-induced protein 10 (IP-10/CXCL10) in HIV regardless of cognition, but elevated CSF interleukin 8 (IL-8/CXCL8) only in HIV-NC but not HAND. Eleven HIV-infected subjects underwent repeat CSF collection six months later and showed strongly correlated longitudinal changes in p-Tau181 and IL-8 levels (R = 0.841). These data suggest reduced IL-8 relative to IP-10 and reduced p-Tau181 to characterize HAND

CSF Cytokines in Aging, Multiple Sclerosis, and Dementia

Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23–86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon–gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes

Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence

Background: HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. Therefore, we focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. Results: A phylogenetic analysis of tat sequences of Southern African (South Africa and Zambia) HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV − 1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries compared to Southeast Asia and broadly paralleled the high incidence of HAD in these countries. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C1084i), a HIV-1C isolate (HIV-1IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV − 1C. Conclusions: We report here, for the first time, that HIV-1C from Southern African countries is genetically distinct from Southeast Asian HIV-1C and that it exhibits a high frequency of variants with dicysteine motif in a key neurotoxic HIV protein, Tat. Our results indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat

Interferon Beta-1b and Childhood Multiple Sclerosis

The long-term treatment with interferon beta-1b of a 7-year-old male with relapsing-remitting multiple sclerosis is documented. Thirty-two months after initiating treatment, he demonstrates dramatic clinical improvement, without relapse, despite high titers of neutralizing antibodies to interferon beta-1b. It appears reasonable to attribute a role in his improvement to interferon beta-1b

A Rationale and Approach to the Development of Specific Treatments for HIV Associated Neurocognitive Impairment

Neurocognitive impairment (NCI) associated with HIV infection of the brain impacts a large proportion of people with HIV (PWH) regardless of antiretroviral therapy (ART). While the number of PWH and severe NCI has dropped considerably with the introduction of ART, the sole use of ART is not sufficient to prevent or arrest NCI in many PWH. As the HIV field continues to investigate cure strategies, adjunctive therapies are greatly needed. HIV imaging, cerebrospinal fluid, and pathological studies point to the presence of continual inflammation, and the presence of HIV RNA, DNA, and proteins in the brain despite ART. Clinical trials exploring potential adjunctive therapeutics for the treatment of HIV NCI over the last few decades have had limited success. Ideally, future research and development of novel compounds need to address both the HIV replication and neuroinflammation associated with HIV infection in the brain. Brain mononuclear phagocytes (MPs) are the primary instigators of inflammation and HIV protein expression; therefore, adjunctive treatments that act on MPs, such as immunomodulating agents, look promising. In this review, we will highlight recent developments of innovative therapies and discuss future approaches for HIV NCI treatment