During the discussion that followed, one or more participants identified several important topics as deserving further investigation. These topics are summarized below in no particular order, other than the sequence in which they were raised during the discussion.
Does neuroAIDS progress in patients who are virally controlled? This begs the more basic question of whether peripheral or CNS virus is the reservoir during latency. A systematic study will be needed to answer these questions. However, troubling data have emerged from the CHARTER study suggesting that controlling the virus is not the same as eliminating the virus (or its effects) and that macrophages/microglia represent a major CNS reservoir of virus. Elyse Singer, University of California, Los Angeles, reported that she sees neurocognitive deficits in about half of her AIDS patients and that it seems to progress even with undetectable levels of CNS and plasma virus. However, there are no clinical guidelines for the treatment of neuroAIDS, and most clinicians do not even screen for it if they encounter peripheral neuropathy. If neurological disease does progress in virally controlled patients, the patients need to be informed.
Unique opportunities for neuroAIDS research in large US cities Immigration has created a single setting with small numbers of all possible populations—Why not study neuroAIDS in these populations in an industrialized setting? However, it is likely that investigators will find that the real problems in this group are not cognitive deficit, but gross psychiatric disease, complicated by IV drugs and other behavioral factors.
International research is vital There is no way to control the epidemic without trained personnel who can transfer existing knowledge as well as acquire new knowledge. In addition, the interaction of HIV and opportunistic infections cannot be properly studied in domestic settings. However, President’s Emergency Plan for AIDS Relief (PEPFAR) has not really helped research, even international research. In general, NIH spends 10% of its AIDS budget on international activities. Should NIMH ask for new money or prioritize the available budget? What are the most important questions for international settings? Progression under ART? Migration of macrophages? Or the curious appearance of strokes and atherosclerosis among young HIV-1 seropositive men in Africa, a phenomenon that may not be unique to Africa?
Do more with available therapeutics Are there better ways to use existing ART to target the CNS and improve their effectiveness against neuroAIDS. Certainly, all new ART and adjuncts should be routinely screened for neuroAIDS indications. Some patients have a variety of cognitive and motor impairments, each of which has its own treatment regimen, some of which involve pretreatment with steroids. We need a more comprehensive, neuroprotective therapy for neuroAIDS that will preserve neurological function and quality of life.
NeuroAIDS is a bigger problem than we thought Current estimates of the incidence of HAND put it at 30% of AIDS patients, which would make it the third most common dementia in the world. Good data are emerging from ACTG 5199, but a more definitive study with standardized data will be needed to define global incidence.
Collect better data on neuroAIDS One participant suggested that neurocognitive categories should be added to the data collected by the International Epidemiologic Databases to Evaluate AIDS. This would require standardized measures to diagnose and quantify neurocognitive impacts. It would also be expensive; and while NIMH would like to make this change, it might be more effective to make better use of existing resources.
Involve the broader community and broaden the research focus NeuroAIDS does not just affect the patient; it also affects their caregivers and medical personnel. However, neurologists and psychiatrists are not dealing with neuroAIDS, despite its many commonalities with Alzheimer’s and multiple sclerosis. There may be clues in the successful treatments of those diseases. By the same token, how can the study of neuroAIDS inform the study of other neurodegenerative diseases? Will it be possible to develop standardized measures, assays, and imaging protocols?
Patients do not die from neuroAIDS Instead, they die from opportunistic infections (OIs), especially internationally, often before they have time to become demented. In addition, OIs add significantly to the cost of treating AIDS patients. Ideally, we should treat HAND and neurological OIs simultaneously. The low-hanging fruit in this area is toxoplasmosis encephalitis, the most common neurological condition in HIV-1-seropositive patients in the ART era. Several therapies are available in the USA, at widely varying prices; but cheaper alternatives will be needed to address this problem in the rest of the world.
We may be seeing a paradigm shift in the study of neuroAIDS Past research has focused narrowly on the virus, and as a result, all available therapeutics target the virus. NeuroAIDS would now appear to be a broader and more complex process of immune dysregulation that involves multiple systems. As a result, neuroAIDS researchers will need to think more globally, in terms of reservoirs, other cell types, neurodevelopment, and other drug targets. To do this, they will need to bring additional scientific disciplines to bear on neuroAIDS and put together interdisciplinary research teams.
Develop better animal models of neuroAIDS Several participants suggested that current animal models do not accurately portray the current, clinical experience of viral control, and chronic inflammation under ART. In SIV, early events determine the neurological outcome, but the virus is in the brain early and death sometimes follows within 30 days. The endotoxemic mouse may be a better (or less expensive) model of chronic CNS inflammation. There is a special need for animal studies to determine when to initiate neuroprotective therapy, as well as for vaccine studies, and in a few years, there will be a demand for additional animals to test the in vivo efficacy of the numerous HIV protein antagonists that will emerge from current research.
Standardization will enhance collaboration NIH and others have invested millions of dollars in developing extensive data sets and specimen collections; but while the cohorts must remain separate, there is no need for the data and specimens to remain separate. NIMH should do more to ensure that data collection produces a research set. It should also support efforts to harmonize and standardize the definitions, categories, measures, assays, and protocols that are used by different collaborations; encourage those collaborations to share data and compile catalogs of their specimen collections; and to make these resources available to outside investigators. One participant suggested that a good initiative in this direction would be for NIMH, NINDS, and NIDA to convene a consensus conference or to sponsor a consensus paper to set out the components of a standard neurological evaluation for HIV patients. Another participant said that this would take 5 to 7 years to get into the scientific literature and suggested that NIH could make it so tomorrow, by merely promulgating the standard itself. The NIH standards could take the form of a “tool box” that identifies all of the validated tests that are available for evaluating the cognitive, verbal, and motor abilities of neuroAIDS patients.
Follow-up of well-characterized cohorts Uncertainty about the progression of HAND during HAART can be addressed through careful tracking of patient cohorts. Natural history (ALLRT, CHAVI, CHARTER) and neuroprotective clinical trial cohorts (ACTG) implement validated clinical, neuropsychologic, and virologic tests that are critical for assessing long-term outcomes. Short-term studies (months) are unlikely to yield definitive conclusions about the effectiveness of neuroprotective strategies in a chronic syndrome such as HAND. Long-term outcomes (years) must be determined in such carefully characterized cohorts.
Involving the vaccine community in CNS studies Vaccine testing in the macaque SIV models provides valuable information about effectiveness of immune-mediated systemic viral load suppression on immunopathogenesis and survival. Similar CNS studies in vaccine cohorts are critical to determine the neuroprotective potential of effective vaccines. Macaque vaccine studies produce tissue specimens and laboratory data that can strongly support correlative and outcome-based studies of CNS pathogenesis. Systematic analyses of CNS tissues in these animals should be aggressively pursued. The CHAVI study of innate immunity markers (120 acute HIV infections/AHI) is defining the kinetics of systemic elevations in acute-phase proteins, cytokines, and chemokines during the earliest stages of infection (transmission, viral eclipse phase). The frequencies and function of peripheral DC, NK, and NKT cells and the kinetics of antibody production are also being examined. These early events could influence CNS invasion, neuroimmune responses, and cognitive outcomes.
What early events influence CNS outcomes? This is among the most difficult questions to answer and it requires longitudinal analyses of recent seroconverters (CHAVI). Functional brain imaging is critical for defining early brain responses to systemic and CNS infection because it is the only method capable of analyzing brain metabolism in real time. However, the necessary technology for such studies is not easily transferable in limited resource settings. Acute HIV infection serological markers of innate immunity (IB) should be examined as associative and predictive markers for neuropathogenesis.
Host responses in the CNS Along with analysis of CNS neurochemical responses by functional imaging, cerebrospinal fluid sampling and analysis are also essential. Long-term follow-up of carefully characterized cohorts (e.g., CHAVI seroconverters) is essential; short-term cohort studies represent a relatively inefficient use of resources. This will determine whether targeted neuroprotection can or should be applied in chronically infected individuals.
When should treatment be initiated? Current criteria for initiation of ART do not consider CNS outcomes as a benchmark of efficacy. Establishing CNS-based criteria for initiation of therapy should be the ultimate goal of neuroprotection strategies. This applies to ART as well as candidate adjunctive neuroprotective drugs as they are developed. Determining neurological outcomes in acute seroconverters (ART treated and untreated) is the critical first step.
Opportunistic infections—optimal and cost-effective treatment The diagnostic criteria will depend on standard laboratory diagnostic tests and cost-effective brain imaging. Preliminary studies support OIs as significant contributors to the morbidity of AIDS in underdeveloped countries. The first priority should be determination of the prevalence of CNS OIs (TB, toxoplasmosis, crytptococcus).
Other complications (i.e., vascular) The effects of HIV and ART accelerate the risk of cardiovascular disease, but the risk of cerebrovascular disease (CVD) and its complications is undefined. Recent studies within the USA suggest an increased risk of CVD, and investigating this risk in patients in underdeveloped countries requires technology transfer and infrastructure development.
Influence of cellular entry on the development of CNS infection The SIV macaque models most closely mimic HIV infection in humans. Both acute and chronic CNS pathogenesis models are useful, and emphasis should be placed on developing antiretroviral drug treatment paradigms that mimic ART regimens and that alter disease course. Defining sources and adequate supplies of drugs is a priority. Other relevant models should be explored but realistically, to date none have fully modeled the steps from HIV neuroinvasion through neurodegeneration.