Jeymohan Joseph

NeuroAIDS in Africa

In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting “NeuroAIDS in Africa.” This meeting was held in Cape Town, South Africa, and was affiliated with the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Presentations began with an overview of the epidemiology of HIV in sub-Saharan Africa, the molecular epidemiology of HIV, HIV-associated neurocognitive disorders (HANDs), and HAND treatment. These introductory talks were followed by presentations on HAND research and clinical care in Botswana, Cameroon, Ethiopia, The Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, and Zambia. Topics discussed included best practices for assessing neurocognitive disorders, patterns of central nervous system (CNS) involvement in the region, subtype-associated risk for HAND, pediatric HIV assessments and neurodevelopment, HIV-associated CNS opportunistic infections and immune reconstitution syndrome, the evolving changes in treatment implementation, and various opportunities and strategies for NeuroAIDS research and capacity building in the region.

Global NeuroAIDS roundtable

In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the “Global NeuroAIDS Roundtable” in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the “Global NeuroAIDS Roundtable”, presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.

HIV eradication symposium: will the brain be left behind?

On 18 July 2014, the National Institute of Mental Health in collaboration with ViiV Health Care and Boehringer Ingelheim supported a symposium on HIV eradication and what it meant for the brain. The symposium was an affiliated event to the 20th International AIDS Conference. The meeting was held in Melbourne, Australia, and brought together investigators currently working on HIV eradication together with investigators who are working on the neurological complications of HIV. The purpose of the meeting was to bring the two fields of HIV eradication and HIV neurology together to foster dialogue and cross talk to move the eradication field forward in the context of issues relating to the brain as a potential reservoir of HIV. The outcomes of the symposium were that there was substantive but not definitive evidence for the brain as an HIV reservoir that will provide a challenge to HIV eradication. Secondly, the brain as a clinically significant reservoir for HIV is not necessarily present in all patients. Consequently, there is an urgent need for the development of biomarkers to identify and quantify the HIV reservoir in the brain. Lastly, when designing and developing eradication strategies, it is critical that approaches to target the brain reservoir be included.

NeuroAIDS in the Asia Pacific Region

Over 8.3 million people living in the Asia Pacific region are human immunodeficiency virus (HIV) positive and up to 40% of these individuals have had prior acquired immunodeficiency syndrome (AIDS) illnesses. Recently endeavors have been made to better characterize the burden of HIV-related neurological disease within the Asia Pacific region and, with this in mind, the NeuroAIDS in Asia and the Pacific Rim workshop was held in Sydney, Australia, as an affiliated event of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. The workshop was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH) of the United States National Institutes of Health and the Australian Government overseas AID program, AusAID. HIV neurologists, infectious disease physicians, pediatricians, psychiatrists, immunologists, virologists, and researchers from 12 countries of the Asia Pacific region (including Australia), the United States, and the United Kingdom attended the meeting. A broad range of topics were addressed, including common HIV neurological disorders, the lack of diagnostic, management, and research infrastructure, central nervous system (CNS) immune restoration disease, pediatric neuroAIDS, and current clinical and laboratory research projects being undertaken within the Asia Pacific region.

NeuroAIDS in Brazil

Brazil has the largest number of HIV cases of any single country in Latin America—over 600,000. Recently, investigators have begun to characterize the extent of neurological morbidity due to HIV in this country. During 2005 and 2006, the U.S. National Institute of Mental Health cosponsored two meetings of experts aimed at summarizing existing knowledge of HIV and its neurological complications in Brazil. Topics addressed ranged from clinical neurobehavioral aspects to molecular biology. Experts attending the meeting considered fruitful directions for future research.

Proceedings from the NIMH symposium on “NeuroAIDS in Africa: neurological and neuropsychiatric complications of HIV”

Despite major advances in HIV-1 treatment, the prevalence of HIV-associated neurocognitive disorders (HAND) remains a problem, particularly as individuals on suppressive treatment continue to live longer. To facilitate discussion on emerging and future directions in HAND research, a meeting was held in Durban, South Africa in March 2015 as part of the Society of Neuroscientists of Africa (SONA) conference. The objective of the meeting was to assess the impact of HIV subtype diversity on HAND and immunological dysfunction. The meeting brought together international leaders in the area of neurological complications of HIV-1 infection with special focus on the African population. Research presentations indicated that HAND was highly prevalent and that inflammatory cytokines and immune-activation played important roles in progression of neurocognitive impairment. Furthermore, children on antiretroviral therapy were also at risk for developing neurocognitive impairment. With respect to the effect of HIV-1 subtype diversity, analyses of HIV-1 clade C infection among South Africans revealed that clade C infection induced cognitive impairment that was independent of the substitution in HIV-1 Trans-Activator of Transcription (Tat; C31S). At the cellular level, a Zambian study showed that clade C infection resulted in reduced brain cell death compared with clade B infection suggesting clade specific variations in mediating brain cell injury. Furthermore, ex vivo Tat protein from clade CRF02_AG, prevalent in West/ Central Africa, exhibited reduced disruption of brain endothelium compared with clade B Tat protein. Discussions shed light on future research directions aimed at understanding biomarkers and disease mechanisms critical for HAND.

HIV-1 Induced CNS Dysfunction: Current Overview and Research Priorities

BACKGROUND Over the past three decades, the clinical presentation of HIV infection of the Central Nervous System (CNS) has evolved. Prior to wide spread use of effective antiretroviral therapy (ART), more than a third of infected individuals exhibited a range of neurocognitive and motor deficits that frequently progressed to severe dementia and paralysis. However, the use of ART has significantly decreased the prevalence of severe forms of HIV-1 associated neurocognitive disorders (HAND). Studies of neurocognitive dysfunction have reported variable prevalence, ranging from 21% to 77.6%, defined primarily by mild to moderate neurocognitive impairment. HIV-associated chronic inflammation and associated neurotoxicity of long term ART, as well as the aging of the HIV-infected population, likely influence the pathogenesis of HAND. Despite significant research efforts directed towards a better understanding of the mechanisms underlying HIV neuropathogenesis, definitive causal pathophysiology of HAND and thus effective prevention or treatment remain elusive. Furthermore, HIV therapeutic research now includes efforts to effect a cure, by eliminating or silencing HIV within infected cells, which must include efforts to target the latently infected cells within the CNS. CONCLUSION Prevention and treatment of the neurological complications of HIV, and eradication of persistent virus from the CNS compartment are major priorities for the HIV-CNS research. Here we give an overview of the progress of research on HIV-CNS disease, define new challenges and research areas, and highlight domestic and global priorities.

Planning Future Strategies for Domestic and International NeuroAIDS Research, July 24-25, 2008

The National Institute of Mental Health in cooperation with the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke organized a meeting on July 24–25, 2008 to develop novel research directions for neuroAIDS research. The deliberations of this meeting are outlined in this brief report. Several critical research areas in neuroAIDS were identified as areas of emphasis. Opportunities for collaborations between large NIH-funded projects were also discussed.

Basic, clinical, and epidemiological studies of progressive multifocal leukoencephalopathy: Implications for therapy

The Neurologic AIDS Research Consortium (NARC) with support from the National Institute of Neurologic Disorders and Stroke (NINDS) organized the first major meeting on the biology of JC virus and progressive multifocal leukoencephalopthy (PML) in Chicago (February 2001). In recognition of the fact that the incidence of PML has increased in the AIDS (acquired immune deficiency syndrome) era, the key goal of this meeting was the integration of current basic and clinical knowledge to facilitate rapid development of therapeutic options. This meeting proved to be enormously successful in updating the basic and clinical scientists on the major issues and challenges of understanding and treating JC virus–induced demyelinating disease. The advent of highly active antiretroviral therapy (HAART) has had significant benefits for AIDS patients due to reduced viral load and increased numbers of CD4 T cells. However, successful treatment of human immunodeficiency virus (HIV) infection is not always associated with an improved outcome for PML patients. Therefore, it is widely believed that an urgent need exists to develop and test additional therapeutic modalities that directly target JC virus. It is this realization that led the National Institute of Mental Health (NIMH), the Office of Rare Diseases (ORD), and the NINDS to convene a second meeting in July 2002 in Portland, Maine, to reassess the current state of basic, clinical, and epidemiologic knowledge in the field. Another important goal of the meeting was

Viral and host genetic factors regulating HIV/CNS disease

The National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke convened a joint symposium entitled “Viral and Host Genetic Factors Regulating HIV/CNS Disease” on November 20–22, 2002 in Washington DC. The purpose of this meeting was to review studies of viral genetics that examined molecular diversity of HIV-1 and how it reflects viral trafficking into the CNS, mechanisms of pathogenesis, and compartmentalized evolution of drug resistance in the context of currently available highly active anti-retroviral therapy (HAART). Research on compartmentalized viral evolution is germane to the ongoing debate concerning viral reservoirs in the central nervous system (CNS) and the potential for reseeding drug resistant strains of HIV-1 to the periphery. The role of HIV-1 diversity in regulating interactions with host receptors on CNS-derived cells and the functional impact on neuropathogenesis were also examined. In addition a session was devoted to highlighting emerging findings that emphasized the impact of host genetic factors on susceptibility and progression of HIV-associated CNS disease. This special issue is devoted to papers elaborating the topics presented at the symposium. These papers not only summarize important recent progress in understanding how host and viral genetics factors influence HIV neuropathogenesis, but they also highlight new emerging questions that will guide future research efforts. Compartmentalization of HIV-1 infection in the CNS/CSF