Biotypes of Central Nervous System Complications in People Living With Human Immunodeficiency Virus (HIV): National Institute of Mental Health Perspectives on Advancing the Future of HIV Healthcare.

Despite effective suppressive antiretroviral therapy, central nervous system (CNS) complications related to human immunodeficiency virus (HIV) remain a significant problem for people with HIV (PWH). Numerous studies have contributed data to define the mechanisms underlying HIV-associated CNS pathophysiology, but causality remains elusive, with no effective therapies to prevent, reduce, or reverse HIV-associated CNS complications. Multiple physiological, clinical, cognitive, behavioral, social, and environmental factors contribute to the observed heterogeneity of adverse CNS outcomes among PWH. The National Institute of Mental Health in collaboration with investigators engaged in research related to HIV associated CNS complications organized a series of meetings to review the state of the science and facilitate the development of biologically based measures to identify the phenotypic heterogeneity of CNS outcomes linked to pathophysiology (biotypes). In this article, we summarize the proceedings of these meetings and explore the precision medicine framework to identify critical factors linked to the etiopathogenesis of CNS outcomes in PWH.

Correction to: Astrocytes as an HIV CNS reservoir: highlights and reflections of an NIMH-sponsored symposium.

In the original article the name of author Lena Al-Harthi was misspelled. It is correct here.

Astrocytes as an HIV CNS reservoir: highlights and reflections of an NIMH-sponsored symposium.

This a summary of a National Institute of Mental Health (NIMH) sponsored symposium that was focused on the role of astrocytes as a reservoir of the human immunodeficiency virus in the brain. The talks were grouped into four themes. The first theme reviewed the evidence for HIV infection of astrocytes and discussed the challenges in the use of traditional methods of immunostaining and in situ hybridization for detection of infected astrocytes. The second theme focused on mechanisms of HIV entry into astrocytes and discussed CD4 independent mechanisms, such as receptor-mediated endocytosis and transmission of HIV by cell-to-cell contact with infected lymphocytes. The third theme focused on epigenetic regulation of HIV latency in astrocytes and other factors, such as cytokines and transcriptional factors regulating HIV replication in astrocytes. The fourth theme focused on therapeutic approaches, such as gene editing to block persistently infected astrocytes. A discussion that followed was focused on major unanswered questions in the field and future directions for 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.

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.

Role of macrophages in HIV pathogenesis and cure: NIH perspectives.

Macrophages play a significant role in HIV infection and contribute to pathogenesis of comorbidities as well as establishment of the viral reservoir in people living with HIV. While CD4+ T cells are considered the main targets of HIV infection, infected macrophages resist the cytopathic effects of infection, contributing to the persistent HIV reservoir. Furthermore, activated macrophages drive inflammation and contribute to the development of comorbidities, including HIV-associated CNS dysfunction. Better understanding the role of macrophages in HIV infection, persistence, and comorbidities can lead to development of innovative therapeutic strategies to address HIV-related outcomes in people living with HIV. In October 2021, the National Institute of Mental Health and the Ragon Institute of MGH, MIT, and Harvard conducted a virtual meeting on role of macrophages in HIV infection, pathogenesis, and cure. This review article captures the key highlights from this meeting and provides an overview of interests and activities of various NIH institutes involved in supporting research on macrophages and HIV.

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.

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.

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.

Highlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA.

CSF HIV escape is a recently recognised phenomenon that suggests that despite suppressive treatment, HIV RNA may be detected in the CNS compartment in some individuals. In rare cases this is associated with clinical neurological disease, while in most cases, neurological consequences are not apparent. Attempts at characterising the biological substrates of CSF escape and further investigating the neurological consequences need to be made to better understand the implications of this condition for the HIV cure agenda as well as for clinical outcomes. The Global CSF HIV-1 Escape Consortium meeting, convened by the US National Institute of Mental Health, was a first step to gather investigators from diverse sites to discuss opportunities for future collaborative work on this emerging issue. To better understand CSF HIV escape and allow cross-site data reconciliation, it will be useful to reach a consensus set of definitions of the distinct forms of CSF escape, without which concerted cross-site efforts are difficult.

Mutational analysis reveals an essential role for the LXXLL motif in the transformation function of the human herpesvirus-8 oncoprotein, kaposin.

Human herpesvirus-8 (HHV-8) is causally linked to Kaposi's sarcoma (KS). Sequence analysis of the genome and subsequent studies revealed several genes including kaposin, with transformation properties in cell culture. In this study, we have analyzed the requirement of Kaposin A for cellular transformation in an effort to understand its contribution towards KS pathogenesis. Comparative analysis of Kaposin with other proteins identified the LXXLL motif spanning from residues 31-35 (LVCLL). The observation that the LXXLL motif is present in nuclear receptor coactivators that mediate the interaction of coactivators with nuclear receptors has prompted us to investigate the relevance of this motif for Kaposin's function(s). Kaposin A coding sequences were cloned into a eukaryotic expression plasmid with the Flag (FL) epitope fused in-frame at the C-terminus (Kap-FL). To evaluate the role of leucine residues in the motif, site-directed mutagenesis was utilized, whereby alanine was substituted for the leucine residues (Kap-AXXAA-FL). Both Kap-FL and Kap- AXXAA-FL exhibited similar levels of expression in cells. Interestingly, the Kap-AXXAA-FL mutant failed to show transforming activity by two independent assays: anchorage-independent growth, and focus formation. Immunofluorescence (IFA) and FACS analysis indicated that Kap-FL was localized around the nucleus and at the cell surface, respectively. However, Kap-AXXAA-FL exhibited diffuse cytoplasmic staining as measured by IFA yet was still detectable on the cell surface by FACS. Ironically, both Kap-FL and Kap-AXXAAFL were able to activate the AP-1 promoter. These results support an important role for the LXXLL motif in the ability of Kaposin to induce transformation.

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.

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.