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.

Methodological and Measurement Advances in Social Determinants of HIV: View from NIH.

Social determinants are increasingly understood as key contributors to patterns of heightened risk for HIV acquisition and suboptimal care and treatment outcomes. Yet, the ability to rigorously model, map and measure these nuanced social dynamics has been a challenge, resulting in limited examples of effective interventions and resource allocation. In 2016, the United States National Institute of Mental Health (NIMH) and the National Institute of Allergy and Infectious Diseases (NIAID) issued a Request for Applications calling for methodological innovations around the social determinants of HIV. In May of 2019, NIMH, in collaboration with American University's Center on Health, Risk and Society and the DC Center for AIDS Research, sponsored a symposium to bring together the funded teams to share accomplishments, distill lessons learned and reflect on the state of the science with other key stakeholders. Presentations focused on causal inference, multi-level analysis and mathematical modeling (Models); geospatial analytics and ecological momentary assessments (Maps); and measurement of social and structural determinants including inequalities and stigmas (Measures). Cross-cutting and higher-level themes were discussed and largely focused on the importance of critical and careful integration of social theory, community engagement and mixed methodologies into research on the social determinants of HIV.

Noncommunicable diseases among HIV-infected persons in low-income and middle-income countries: a systematic review and meta-analysis.

OBJECTIVE: To appropriately identify and treat noncommunicable diseases (NCDs) among persons living with HIV (PLHIV) in low-and-middle-income countries (LMICs), it is imperative to understand the burden of NCDs among PLHIV in LMICs and the current management of the diseases. DESIGN: Systematic review and meta-analysis. METHODS: We examined peer-reviewed literature published between 1 January 2010 and 31 December 2016 to assess currently available evidence regarding HIV and four selected NCDs (cardiovascular disease, cervical cancer, depression, and diabetes) in LMICs with a focus on sub-Saharan Africa. The databases, PubMed/MEDLINE, Cochrane Review, and Scopus, were searched to identify relevant literature. For conditions with adequate data available, pooled estimates for prevalence were generated using random fixed effects models. RESULTS: Six thousand one hundred and forty-three abstracts were reviewed, 377 had potentially relevant prevalence data and 141 were included in the summary; 57 were selected for quantitative analysis. Pooled estimates for NCD prevalence were hypertension 21.2% (95% CI 16.3-27.1), hypercholesterolemia 22.2% (95% CI 14.7-32.1), elevated low-density lipoprotein 23.2% (95% CI 15.2-33.6), hypertriglyceridemia 27.2% (95% CI 20.7-34.8), low high-density lipoprotein 52.3% (95% CI 35.6-62.8), obesity 7.8% (95% CI 4.3-13.9), and depression 24.4% (95% CI 12.5-42.1). Invasive cervical cancer and diabetes prevalence were 1.3-1.7 and 1.3-18%, respectively. Few NCD-HIV integrated programs with screening and management approaches that are contextually appropriate for resource-limited settings exist. CONCLUSION: Improved data collection and surveillance of NCDs among PLHIV in LMICs are necessary to inform integrated HIV/NCD care models. Although efforts to integrate care exist, further research is needed to optimize the efficacy of these programs.

Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research.

The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community.

Integrating behavioral and biomedical research in HIV interventions: challenges and opportunities.

Recent clinical trials have demonstrated overwhelming success of biomedical tools to prevent the spread of HIV infection. However, the complex and somewhat disparate results of some of these trials have highlighted the need for effective integration of biomedical and behavioral sciences in the design and implementation of any future intervention trial. Integrating behavioral and biomedical sciences will require appropriate behavioral theories that can be used in the context of biomedical clinical trials and multidisciplinary teams working together from the earliest stages of trial design through to completion. It is also clear that integration of behavioral science will be necessary to implement prevention at the population level and reverse the HIV epidemic.

Increase of C1q biosynthesis in brain microglia and macrophages during lentivirus infection in the rhesus macaque is sensitive to antiretroviral treatment with 6-chloro-2',3'-dideoxyguanosine.

Complement activation in the brain contributes to the pathology of neuroinflammatory and neurodegenerative diseases such as neuro-AIDS. Using semiquantitative in situ hybridization and immunohistochemistry, we observed an early and sustained increase in the expression of C1q, the initial recognition subcomponent of the classical complement cascade, in the CNS during simian immunodeficiency virus (SIV) infection of rhesus macaques. Cells of the microglial/macrophage lineage were the sources for C1q protein and transcripts. C1q expression was observed in proliferating and infiltrating cells in SIV-encephalitic brains. All SIV-positive cells were also C1q-positive. Treatment with the CNS-permeant antiretroviral agent 6-chloro-2',3'-dideoxyguanosine decreased C1q synthesis along with SIV burden and focal inflammatory reactions in the brains of AIDS-symptomatic monkeys. Thus, activation of the classical complement arm of innate immunity is an early event in neuro-AIDS and a possible target for intervention.

Brain virus burden and indoleamine-2,3-dioxygenase expression during lentiviral infection of rhesus monkey are concomitantly lowered by 6-chloro-2',3'-dideoxyguanosine.

Increased kynurenine pathway metabolism has been implicated in the aetiology of lentiviral encephalopathy. Indoleamine-2,3-dioxygenase (IDO) initiates the increased production of kynurenine pathway metabolites like quinolinic acid (QUIN). QUIN itself is elevated in AIDS-diseased monkey and human brain parenchyma and cerebrospinal fluid at levels excitotoxic for neurons in vitro. This study investigates the cellular origin of IDO biosynthesis in the brain of rhesus monkeys infected with simian immunodeficiency virus (SIV) and explores the effects of CNS-permeant antiretroviral treatment. IDO transcript and protein were absent from the brain of non-infected and SIV-infected asymptomatic monkeys. IDO biosynthesis was induced in the brain of monkeys exhibiting AIDS. Nodule and multinucleated giant cell-forming macrophages were the main sources of IDO synthesis. Treatment with the lipophilic 6-chloro-2',3'-dideoxyguanosine suppressed IDO expression in the brain of AIDS-diseased monkeys. The effectiveness of this treatment was confirmed by the reduction of virus burden and SIV-induced perivascular infiltrates, mononuclear nodules and multinucleated giant cells. Our data demonstrate that brain IDO biosynthesis is induced in a subset of monocyte-derived cells, depends on viral burden and is susceptible to antiretroviral treatment. Thus, IDO induction is associated with reversible overt inflammatory events localized to areas of active viral replication in the SIV-infected brain.

Workshop report: The effects of psychological variables on the progression of HIV-1 disease.

The reciprocal interactions between the neuroendocrine, immune, and autonomic nervous systems are complicated, yet worthy of examination. A body of literature suggests that psychological factors such as stress, or psychiatric conditions such as major depression, may influence the immune system thereby altering host susceptibility to viral, or other types of infection. Alternately, in an attempt to limit infection and replication, the anti-viral host response, via innate and acquired immunity and subsequent release of pro-inflammatory cytokines and additional anti-viral mediators, may affect mood, cognition emotion, and possibly precipitate a psychiatric disorder. In order to address what is known regarding neuroendocrine-immune interactions in the context of HIV infection, the Center for Mental Health Research on AIDS convened a panel of scientists from diverse areas of expertise. Their primary charge was to examine whether stress-induced activation of the neuroendocrine system affects the immune system in a manner that negatively influences HIV disease progression, and whether HIV infection influences the central nervous system and behavior. The ensuing report summarizes their deliberations as they discussed the current body of information and identified outstanding critical questions in the areas of research. The group consensus was that the biological mediators of psychological status can play an important role in mediating HIV disease progression, particularly in subgroups of vulnerable patients; furthermore, they identified candidate biological mediators and mechanisms of disease progression. The Workgroup outlined the inherent challenges and limitations of such research and provided recommendations as to the future directions of research utilizing human, animal, and in vitro models of HIV-1 infection and stress.