[Emerging Infectious Diseases * Volume 3 * Number 3 * July - September 1997]

Commentaries


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Host Genes and HIV Infection: Implications and Applications
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Disease emergence often involves the introduction of a familiar microbial
agent into a novel ecologic niche or the evolution of a previously
unrecognized microorganism in what had ostensibly been a stable
environment. So accustomed are we to emergence brought on by changes in an
agent or its environment that we overlook effects of the third force of
causality -- the host. The easy justification for our relative indifference
to the contributions of the host has been that host characteristics,
especially those under genetic regulation, have less potential for rapid,
epidemiologically significant evolution; moreover, the genetic mechanisms
of host response have been too poorly elucidated to permit rational
manipulation.

The emergence of human immunodeficiency virus (HIV), however, has been
different. HIV has "emerged" so masterfully by exploiting fundamental
vulnerabilities in the immune system of primates that contributions of host
immunity cannot be ignored. The virus has apparently evolved from its
simian cousins toward a form that is extraordinarily well adapted to humans
in several ways: 1) it rapidly replicates, ensuring high mutation rates
within an individual host; 2) it is readily transmissible from person to
person in the absence of an animal vector; and 3) because it is not
invariably lethal before the age span for most human reproduction,
evolutionary pressure toward radical change, attenuation, or disappearance
from the population is not strong. The enormous epidemiologic implications
of these basic facts have become obvious during the decade and a half of
our struggle against the virus. We cannot control it by manipulating its
macroenvironment as we might a parasite carried by a vector or waterborne
virus. Interrupting local transmission by setting up psychosocial or
mechanical barriers has limited potential. Despite the recent highly
encouraging advances in antiretroviral therapy, direct and complete
pharmacologic or immunologic eradication of the virus worldwide is still an
untenable prospect. So we have little choice but to search for biologic
strategies that reliably interdict the host-virus relationship; to
accomplish that will require insight into the fundamental mechanisms of
that interaction -- knowledge at the level of viral and host genetics.
Indeed, modulating genetically determined features of the immune response
to the virus may represent the best hope for its ultimate conquest. Recent
breakthroughs have accelerated the accumulation of the knowledge necessary
to accomplish that aim. In this issue of Emerging Infectious Diseases, the
review of current information by McNicholl and colleagues about the
genetics of virus-host interaction concentrates on the recently described
variations in genes encoding the human -chemokine receptors, appropriately
providing perspectives from both laboratory and public health sciences. The
quest to identify immunogenetic determinants of the host-virus interaction
in HIV infection actually began with studies of the human major
histocompatibility complex (HLA) soon after the AIDS epidemic was
recognized, but in the past 2 years molecular technology has been focused
on promising loci in the chemokine receptor gene systems, as well as in
HLA. The importance of polymorphic variants of these host genes in
determining whether the infection occurs and how rapidly it proceeds has
been established.

The extreme polymorphism and other related properties of HLA have made it
more difficult than expected to demonstrate the full influence of products
of these genes on the initiation and progression of HIV infection; however,
current work on HLA is slowly confirming that expectation, which is
reasonably based on 25 years of research on the role of antigen-presenting
genes in a whole range of autoimmune, inflammatory, and infectious
processes. In contrast, -chemokines and the genetically mediated variation
in their receptors were recognized only recently, but the initial
observations and numerous confirmatory reports of their involvement in HIV
infection have been compelling, and there is undoubtedly more to come.

The most important consequence of these recent discoveries has been to
foster an aggressive academic and industrial enterprise aimed at developing
a safe, clinically beneficial immunomodulation of -chemokines and their
receptors in both infected and uninfected persons. The relative simplicity
of the gene system, the frequency of the apparently protective variant
(i.e., the 32bp deletion) of CCR5, and the seemingly nonessential nature of
either the wild or mutant form of the receptor for normal immune function
have suggested that emulation of the unreceptive mutant state (e.g., by
saturating the normal receptor with a specific high affinity chemokinelike
antibody) might interrupt viral penetration and replication. The
implication here is clear. If antibodies to the normally functioning CCR5
can block viral attachment and prevent infection of the cell most critical
to propagation of the agent without collateral damage to vital host immune
function, a vaccine capable of inducing those antibodies without serious
adverse effects could represent an adjunct to the current antiretroviral
therapeutic agents and a major breakthrough toward a primary preventive
strategy not dependent on changing personal behavior. The optimism and
publicity that often accompany this kind of success must be tempered with
caution: the strategy depends heavily on whether HIV can circumvent this
hurdle by utilizing CXCR4 or other alternative pathways of entry into
cells.

However, even if the promise of preventive and therapeutic intervention
based on chemokine receptor manipulation is not soon fulfilled, another
tangible benefit inherent in the discovery of factors like the receptor
variants and HLA polymorphisms should not be overlooked. These genetic
factors, however amenable or resistant to clinical manipulation they may
prove to be, have true prognostic value and therefore offer a clear,
immediate opportunity to refine our ongoing evaluations of other promising
therapeutic or preventive measures. Consider the randomized trial of a new
chemotherapeutic agent, intentionally designed to compare its average
efficacy in all trial participants with the average efficacy of the
conventional agent. Because HIV-1-infected persons who are heterozygous for
the CCR5-deletion progress more slowly than those who carry only the wild
type, stratifying the study population according to the presence or absence
of the deletion, either during randomization or during analysis, should
clarify whether the benefit of the experimental regimen in study
participants who also carry the more favorable genetic trait is additive or
even synergistic. Moreover, in clinical settings other than randomized
trials, the additional information about receptor deletion status may be
essential to analyzing the effects of interventions under evaluation or to
customizing patient care.

The possibility that the genotype information might be used to refine the
observations from current clinical research and to individualize the
management of HIV-infected or even uninfected persons has also raised
questions about whether typing more routinely might be appropriate.
Although the concept of identifying a predisposing factor and modifying
recommendations for treatment or prophylaxis accordingly is well
established in the management of infectious diseases, screening for a
particular genetic trait is not. So another implication of the research on
host genetics in HIV infection is that it will probably draw health
professionals into many of the same opportunities, obligations, and
ultimately controversies that already surround the discovery of genes
predisposing to cancer or chronic metabolic diseases like hemochromatosis.
What may distinguish genetic screening in the context of infectious
diseases from the rest, and even impose greater urgency for decisions about
genetic testing, is that carriers of a genetic trait conferring relatively
high risk may be readily capable of taking explicit precautions to avoid
exposure to an identifiable etiologic agent. In short, in some situations
the payoff may be more immediate.

The discovery of host genes that exert major influence on the acquisition
and progression of HIV infection has radically altered our thinking about
the pathogenesis of retroviral infection. The prognostic value of these
genetic factors should be incorporated into the assessment of interventions
to control the infection. The intense effort under way to translate
knowledge of these human genetic traits into clinical benefit for
HIV-infected and uninfected persons reflects a new rationale for research
on emerging infectious diseases: consider the host, as well as the agent
and the environment.

Richard A. Kaslow
University of Alabama at Birmingham, Birmingham, Alabama, USA
Controversies in the Management of Cysticercosis

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Controversies in the Management of Cysticercosis
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Cysticercosis, an infection caused by larvae of the pork tapeworm Taenia
solium in human tissues, is a common cause of neurologic disease in most
non-Muslim developing countries, where it accounts for more than one-third
of adult-onset epilepsy cases (1). Cysticercosis is increasingly diagnosed
in patients in industrialized nations; persons who have never left the
United States as well as visitors to disease-endemic regions are at risk.
Traditionally considered an exotic disease, this infection now accounts for
up to 2% of neurologic/neurosurgical admissions in southern California (2)
and more than 1,000 cases per year in the United States (3). Further away
from disease-endemic regions, an outbreak of cysticercosis among orthodox
Jews living in New York City was reported after food was contaminated with
T. solium eggs by immigrant cooks infected with the pork tapeworm (4);
these carriers may have been completely unaware of their infections.
Neurocysticercosis has been reported in AIDS patients, but
immunosuppression does not appear to increase the incidence of this
infection. Once cysticercosis is diagnosed, treatment may be necessary, but
optimal therapy and particularly the role of cestocidal drugs is
controversial. In this commentary, we discuss current options in the
treatment of established cysticercosis.

The clinical and pathologic features of neurocysticercosis vary, depending
on the inflammatory response around cysticerci, their number, size, and
location. The presence of viable, living cysticerci in the central nervous
system usually does not cause symptoms (5). In contrast, inflammation
around degenerating cysticerci may have severe consequences, including
focal encephalitis, edema, and vasculitis. The most frequent symptom is
epilepsy. However, neurocysticercosis can cause a wide variety of clinical
syndromes from chronic meningitis and cranial nerve palsies to spinal
infarction and symptoms due to either a mass effect or, particularly in
racemose disease, raised intracranial pressure. Such variable clinical
features necessitate further investigations to make a diagnosis before
treatment.

The diagnosis may be made by excision biopsy of subcutaneous cysticerci,
which are found in 4% to 25% of patients with neurocysticercosis (the
percentages are higher in Asia than in Latin America). However, radiologic
and serologic tests are usually required for diagnosis unless biopsy of a
central nervous system lesion is possible. Computed tomography visualizes
living cysticerci as hypodense lesions not enhanced with intravenous
contrast; a small, hyperdense scolex may be observed within a living cyst
(6). Degenerating cysticerci which are more often symptomatic are isodense
or hyperdense, and edematous inflammation around them usually causes ring
or nodular enhancement by intravenous contrast (5). Magnetic resonance
imaging provides detailed images of living and degenerating cysticerci, as
seen in a heavily infected patient (Figure), but may not detect calcified,
destroyed cysticerci (3). An immunoblot diagnostic test on serum has been
shown to have greater than 98% sensitivity and specificity (7). However, in
patients with single ring-enhancing lesions, sensitivity falls to 60% to
80%. Sensitivity is also reduced if cerebrospinal fluid rather than serum
immunoblot is used.

 [Image]
Figures Not Available in Ascii
 Figure. Magnetic resonance                          
 image of a patient with neurocysticercosis demonstrating multiple
cysticerci within the  brain.     

  
               
The treatment of established neurocysticercosis   is controversial and probably depends on the
associated inflammatory reaction as well as
clinical and pathologic features. Symptomatic therapy with conventional anticonvulsant drugs
 is indicated to control epilepsy. Symptoms often result from self-limiting
inflammation around a degenerating cysticercus (3,5). Raised
intracranial pressure caused by this local reaction usually responds to
oral corticosteroids. Steroids have been given chronically in occasional
cases of persistent intracranial inflammation. Surgery also has a role: a
ventriculoperitoneal shunt relieves obstructive hydrocephalus, although
shunt blockage is common when the cerebrospinal fluid protein is elevated.
Because inflammation associated with medical therapy may threaten vision,
surgery has been used to excise intraocular cysticerci. Asymptomatic
subcutaneous or intramuscular cysticerci do not require treatment.

Cestocidal therapy with praziquantel (50 mg/kg/day tid orally for 14 days)
or albendazole (15 mg/kg orally tid/bid for 8 to 15 days) accelerates
radiologic disappearance of viable intracranial cysticerci. Albendazole may
have slightly greater efficacy and is generally less expensive than
praziquantel. Cestocidal treatment combined with symptomatic care is
associated with a good clinical outcome (8,9). However, these nonrandomized
trials were not optimally controlled, and a similarly benign clinical
course has been described after symptomatic treatment alone in both adults
(5) and children (10). Furthermore, randomized placebo controlled trials
with selected patients have shown no clinical (11) or radiologic (12,13)
benefit from the addition of cestocidal therapy to symptomatic care. A
problem with cestocidal therapy is that it causes influx of inflammatory
cells around cysticerci, which is often associated with transient clinical
deterioration (8). Rarely, this may be fatal in heavy infections, despite
administration of corticosteroids, a common practice to minimize adverse
effects (6). Although coadministering corticosteroids reduces blood levels
of praziquantel and increases those of albendazole, these effects do not
appear to be relevant clinically. Therefore, the immunologic basis has yet
to be determined for the inflammation around cysts when they die or are
killed by cestocidal treatment (14).

Although recommendations cannot yet be definitive, available evidence
suggests that viable, intact cysticerci that cause epilepsy or other
symptoms can be treated with cestocidal therapy, especially if they are
causing mass effect. If cestocidal treatment is instituted, there is no
reason to avoid the use of steroids. These should always be administered
before cestocidal therapy is given to patients with multiple viable
intracranial cysticerci because the sudden and simultaneous death of these
parasites would otherwise cause inflammation, which can be fatal. In
contrast, when untreated patients have neurologic symptoms and radiologic
evidence of inflammation around a degenerating cysticercus, the parasite
has probably already died
, and cestocidal therapy is unlikely to be of
benefit. In such cases, an expectant policy is reasonable: symptomatic
therapy alone for 6 to 12 weeks, unless the patient's condition worsens. A
repeat computed tomography scan then usually shows reduction in size or
disappearance of a degenerating cysticercus (12,13,15). If improvement has
not occurred, then empirical cestocidal chemotherapy may be considered, and
possible alternative diagnoses such as tuberculosis should be entertained.
Intracranial calcifications and lesions that show ring enhancement on
neuroimaging are not living parasites and probably do not warrant
cestocidal therapy.

This approach to cestocidal therapy is controversial, and the results of at
least one ongoing, double-blind, randomized placebo-controlled trial are
keenly awaited. Even when the value of cestocidal therapy is firmly
established or refuted, new antiinflammatory treatments will require
therapeutic approaches to be reevaluated. A greater understanding of the
pathogenesis of this condition is a prerequisite to developing effective
therapy to control inflammation around degenerating cysticerci.

Carlton Evans,* Hector H. Garcia, Robert H. Gilman, and Jon S.
Friedland1
*University of Cambridge Clinical School, Cambridge, United Kingdom;
Instituto de Ciencias Neurologicas, Lima, Peru;
Universidad Peruana Cayetano Heredia, Lima, Peru;
Johns Hopkins University School of Hygiene and Public Health, Baltimore,
USA; and
Royal Postgraduate Medical School, Hammersmith Hospital, London, United
Kingdom

References

  1. Garcia HH, Gilman R, Martinez M, Tsang VCW, Pilcher JB, Herrera G et
     al. Cysticercosis as a major cause of epilepsy in Peru. Lancet
     1993;341:197-200.
  2. McCormick GF. Cysticercosis: review of 230 patients. Bulletin of
     Clinical Neurosciences 1985; 50:76-101.
  3. Shandera WX, White AC, Chen JC, Diaz P, Armstrong R.
     Neurocysticercosis in Houston, Texas. Medicine 1994;73:37-52.
  4. Schantz PM, Moore AC, Munoz JL, Hartman BJ, Schaefer JA, Aron AM, et
     al. Neurocysticercosis in an orthodox Jewish community in New York
     City. N Engl J Med 1992;327:692-5.
  5. Kramer LD, Locke GE, Byrd SE, Daryabagi J. Cerebral cysticercosis:
     documentation of natural history with CT. Radiology 1989;171:459-62.
  6. Wadia N, Desai S, Bhatt M. Disseminated cysticercosis: new
     observations, including CT scan findings and experience with treatment
     by praziquantel. Brain 1988;111:597-614.
  7. Tsang VCW, Garcia HH. Immunoblot diagnostic test (EITB) for Taenia
     solium cysticercosis and its contribution to the definition of this
     under-recognized but serious public health problem. In: Garcia HH,
     Martinez SM (editors). Teniasis/ Cisticercosis por T. solium. Lima:
     Ed. Universo;1996. p. 259-69.
  8. Sotelo J, Escobedo F, Rodriguez J, Torres B, Rubio F. Therapy of
     parenchymal brain cysticercosis with praziquantel. N Eng J Med
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  9. Vasquez V, Sotelo J. The course of seizures after treatment for
     cerebral cysticercosis. N Engl J Med 1992;327:696-702.
 10. Mitchell WG, Crawford TO. Intraparenchymal cerebral cysticercosis in
     children: diagnosis and treatment. Pediatrics 1988;82:76-82.
 11. Carpio A, Santillan F, Leon P, Flores C, Hauser A. Is the course of
     neurocysticercosis modified by treatment with antihelminthic agents?
     Arch Intern Med 1995;155:1982-8.
 12. Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in
     neurocysticercosis. Neurology 1994;44:1344-6.
 13. Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in single CT ring
     lesions in epilepsy. Natl Med J India 1995;8:255-8.
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     neurology. Amsterdam: Elsevier; 1996. p. 155-64.
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