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[Microbiology Research 2011; 3:e11] [page 41]
Gliomas and brain lymphomas
in HIV-1/AIDS patients:
reflections from a 20-year
follow up in Mexico and Brazil
Filiberto Cedeno-Laurent,1,2
J. Roberto Trujillo2,3
1Harvard Medical School, Boston, MA;
2Pan-American Society for
Neurovirology, Washington, DC;
3TruBios Research Institute, Johns
Hopkins University, MCC, Rockville,
Maryland, USA
Abstract
Opportunistic infections and invasive pri-
mary tumors represent major causes of mor-
bidity and mortality in HIV-1-infected individu-
als. HIV-1 involvement of the central nervous
system (CNS) affects nearly half of seroposi-
tive patients, being the primary CNS lym-
phoma (PCNSL) a hallmark neoplasia of this
population. Interestingly, the incidence of
other brain tumors (e.g. gliomas) is exceed-
ingly rare in AIDS patients, and their co-mor-
bidity has been limited to case reports. Here,
we share our 20-year experience following
brain tumors in HIV-1/AIDS patients from
major referral hospitals in Mexico and Brazil.
Additionally, we provide the most updated com-
pilation of reported glioma cases in AIDS
patients, with a thorough epidemiological
analysis. Furthermore, we discuss HIV-1-driv-
en mechanisms that would theoretically
increase malignant transformation of glial
cells; while offering newly reported explana-
tions as to why protease inhibitors, key compo-
nents of multi-drug anti-retroviral schemes,
may be responsible for such a low co-incidence
of gliomas in HIV-1 infected individuals.
Review
Neurocognitive impairment remains a
major burden for HIV-1/AIDS patients. Even
when highly active antiretroviral therapy
(HAART) has become widely available, neuro-
logical manifestations affect up to 50% of
seropositive individuals.1,2 The spectrum of
HIV-1-associated neurological disorders is
wide, and encompasses complications that can
be either primarily related to the retrovirus
itself (e.g. AIDS dementia complex), or sec-
ondary to opportunistic infections, malignant
neoplasms, or the reconstitution of the
immune system.3-5 Over the last 20 years, as
we have followed the AIDS epidemic develop all
over the world, we have noticed clear-cut dif-
ferences in the incidence, prevalence and clin-
ical presentations of neurological complica-
tions reported among industrialized nations to
those reported from developing countries.2,6,7
Such dramatic differences depend on numer-
ous factors that include: the location of the
reporting institution, availability to HAART,
diagnostic tools, treatment guidelines, and the
endemic microbiological repertoire.4,8-11
As HIV-1 infection progresses, defective
immunosurveillance mechanisms favor
uncontrolled proliferation of malignant cells.
Importantly, Epstein Barr virus, the causative
agent of infectious mononucleosis, induces
aberrant genotypical changes and malignant
transformation on infected B cells within the
CNS.12 Inherent to the immunocompromise
experienced in the context of HIV-1 infection,
these malignant cells undergo uncontrolled
clonal expansion forming extranodal foci of
lymphoproliferative cells that may give rise to
primary CNS lymphomas (PCNSL).
Importantly, this neoplasm is exclusively
observed in severely immunocompromised
populations, and its presence was found in
~5% of HIV-1 seropositive patients before the
introduction of HAART (Figure 1).13
Conversely, primary intracranial tumors
derived from other cell lineages are rarely
developed in HIV-1/AIDS patients, with a total
number of 55 reported cases, ever since the
epidemic started in the early 1980’s.2,6,14-36
Gliomas, the most common type of primary
brain neoplasm reported in otherwise healthy
individuals,33 arise from malignant transfor-
mation of neuroectodermal-derived supporting
cells. The pathogenesis of these tumors has
been associated with mutations in the p53
tumor suppressor gene,37 or the p16/RB/E2F
pathway.38 While the annual incidence of
gliomas in the general population is reported
to be around 3.85 cases per 100,000 individu-
als,39 malignant gliomas, including glioblas-
toma multiforme (the most common type of
glioma), do not appear to be in the list of dif-
ferential diagnoses of an occupying brain
lesion in HIV-1/AIDS patients.
Such a rare coincidence obliged us to per-
form a systematic retrospective review and
careful analyses of the reported brain gliomas
in HIV-1 seropositive individuals, comparing
populations from industrialized nations with
two Latin American countries with universal
access to HAART, Mexico and Brazil.
In addition, we discuss relevant evidence
that would theoretically support an enhanced
incidence of gliomas in HIV-1/AIDS patients,
while offering alternative perspectives based
on recent publications, which may offer
insights into the factors promoting a protective
activity for the development of gliomas in
seropositive patients under HAART.
NeuroAIDS in Mexico, a retrospec-
tive view of primary central nerv-
ous system lymphoma and glioma
cases reported in major referral
health institutions
A few years after the first AIDS cases were
reported in the early 1980s, HIV-1 spread south
of the US border. Infectious-disease special-
ists experienced major challenges, as the array
of clinical manifestations exhibited by HIV-
1/AIDS patients in Latin America differed from
those observed in US-based health institu-
tions. Importantly, we performed one of the
first studies depicting such discrepancies.2In
that report, a broad comparison of HIV-1-relat-
ed neurological manifestations among
American and Mexican seropositive patients
was depicted in a cross-sectional and retro-
spective study that included 500 cases from
Houston, Texas, and 120 cases from a cohort in
Mexico City. Clinical reports, laboratory and
imaging data of HIV-1 patients experiencing
neurological manifestations concluded that
the prevalence of PCNSL was dramatically
higher in the US population than it was in
Mexico (8.4% vs. 2.5%), while opportunistic
infections such as intracranial tuberculomas
were observed exclusively in the Mexican
cohort.2Of note, no gliomas were found in the
Mexican population, while 2 cases of gliomas
were reported in the American cohort2
(Figures 2-3).
Years later, another retrospective analysis of
AIDS patients evaluated at the National
Institute of Neurological Diseases in Mexico
City during a 9-year time frame (1990-1998),
found a PCNSL prevalence of 1.3% (Figure 1),
with an identical prevalence for gliomas (1.3%,
2/149).34 Notably, a case of glioblastoma multi-
forme and an oligodendroglioma were reported
in this Mexican study (Figure 4). More recent-
ly, a large retrospective study suggested a sig-
nificant reduction in the prevalence of PCNSL
Microbiology Research 2011; volume 3:e11
Correspondence: J. Roberto Trujillo, Pan-
American Society for Neurovirology, Washington,
DC, USA. Tel: +1.240.753.4007.
E-mail: trujillo@pasnv.org
Key words: Lymphomas, gliomas, HIV-1, AIDS.
Received for publication: 4 July 2011.
Revision received: 29 July 2011.
Accepted for publication: 29 July 2011.
This work is licensed under a Creative Commons
Attribution NonCommercial 3.0 License (CC BY-
NC 3.0).
©Copyright F. Cedeno-Laurent and J.R. Trujillo, 2011
Licensee PAGEPress, Italy
Microbiology Research 2011; 3:e11
doi:10.4081/mr.2011.e11
Non-commercial use only
[page 42] [Microbiology Research 2011; 3:e11]
(0.3%) (Figure 1), an effect attributed indi-
rectly to the widespread use of HAART.41 Since
1998, no more glioma cases have ever been
reported in AIDS patients from any health cen-
ter in Mexico (Figure 2). Similarly, we have
also followed up AIDS cases for 15 years in a
major referral institution located in Monterrey,
the third largest city in the Mexico.
Collectively, in over 20 years of AIDS epidemic
only 2 cases of gliomas have ever been report-
ed in Mexico (Figures 2-3). This picture is
similar to other developing nations in Africa
and Asia where the number of reported cases
does not parallel their close surveillance and
thorough experience in neuroAIDS (Figure 3).
Brazil, a different country with a
similar story
According to the United Nations Programme
on HIV/AIDS, Brazil has between 600,000 and
890,000 people living with AIDS.41 Importantly,
this Latin American Country has free and uni-
versal access to HAART, situation that allows
measuring the impact of AIDS treatment in the
prevalence of neurological manifestations,
including primary tumors. During the past 15
years, over 50,000 patients have been admitted
to the infectious-disease service of Instituto
Emilio Ribas in Sao Paulo. A high number of
patients undergo extensive laboratory and
imaging workups for suspected intracranial
masses, being CNS toxoplasmosis, cryptococ-
cosis and progressive multifocal leukoen-
cephalopathy the most common diagnoses.
Moreover, other comprehensive studies per-
formed in Rio de Janeiro have reported fre-
quencies of PCNSL of ~4%.42 In over 20 years
of AIDS epidemic in Brazil, just a single case of
glioma has been reported in HIV-1 seropositive
individuals35 (Figure 2), reproducing a phe-
nomenon observed throughout most of the
developing world (Figure 3).
Gliomas and HIV-1, is highly active
antiretroviral therapy responsible
for their low co-incidence?
While HIV-1-driven defective immunosur-
veillance generally favors tumor growth and
metastasis, cumulative evidence of over 20
years following the AIDS epidemic demon-
strates that HIV-1-infected individuals rarely
develop gliomas.43 Nevertheless, HIV-1 tropism
and infectivity in the brain is not limited to
microglia/macrophages, but has been shown to
also include astrocytes, which represent a
potential reservoir for further productive infec-
tion.44,45 In fact, astrocytes have been reported
to be preferentially infected by virulent HIV-1
T-tropic strains through different interactions
via the V3 loop,46 and undergo enhanced
malignant proliferation in vitro via Nef-medi-
ated mechanisms.47 Furthermore, HIV-1-driv-
en cytokines like TNF-α, and TGF-βmay pro-
mote oligodendrocytic differentiation and pro-
liferation, theoretically favoring tumor devel-
opment.43,48 However, recent evidence
unveiled a direct mechanism responsible for
controlling glioma growth in HIV-1/AIDS
patients.49,50 These independent studies depict
two ways by which protease inhibitors; med-
ications commonly used in combination thera-
py with reverse transcriptase inhibitors to
dampen HIV-1 infectivity, can abrogate glioma
growth. First, Pyrko P, et al., described how
Nelfinavir and Atazanavir induce apoptosis in
gliomas by triggering endoplasmic reticulum
stress.49 Concomi tantly, Pore N, et al.,
described how Nelfinavir and Amprenavir
decreased vascular endothelial growth factor
(VEGF) and hypoxia-inducible factor (HIF)-1
alpha expression, leading to impaired angio-
genesis in glioblastoma multiforme tumors
injected into nude mice.50 Nonetheless, while
these experimental data reproduces in vivo
effects seen in HIV-1/AIDS patients under
HAART, further detailed mechanisms by which
protease inhibitors might prevent glioma
development remain to be elucidated.
Review
Figure 1. HAART
has reduced the
number of PCNSL
cases in AIDS
patients. Graphi cal
representation of
the prevalence of
PCSNL in patients
with HIV-1/AIDS
during 3 decades.
References are
indicated within
brackets.
Figure 2. Reports
of gliomas in HIV-
1/AIDS patients
follow a Gaussian
distribution dur-
ing the first three
decades of the epi-
demic. Graphical
representation of
the total number of
gliomas reported
in Mexico/Brazil
and the rest of the
world, classified
per decade.
References are
indicated within
brackets.
Figure 3. Gliomas
in HIV-1/AIDS
patients are more
commonly report-
ed in Western
Industrialized
World. Graphical
representation of
the cumulative
cases of gliomas
reported in AIDS
patients and their
distribution per
continent. Refere -
nces are indicated
within brackets.
Non-commercial use only
[Microbiology Research 2011; 3:e11] [page 43]
Discussion
While primary CNS lymphomas have been a
major cause of morbidity in HIV-1/AIDS
patients; the incidence of gliomas, the most
prevalent brain tumor in seronegative popula-
tions, has always been negligible. With a
cumulative number of 55 reported gliomas in
AIDS patients ever since the beginning of the
epidemic, we hypothesize that there may be a
protective role of HIV-1 that restrains glioma
growth (Figures 2-4). Importantly, we have
noticed an important trend; glioma cases were
specially reported from Western European
Countries and the US during the period com-
prising the years 1991-2000, where most peo-
ple still did not have full access to HAART
(Figure 4). Interestingly, between the years
2001 and 2010, where HAART became widely
available, only 5 out of 55 total glioma cases
were reported (Figure 2). Furthermore, our
analysis of the reported gliomas according to
their histological classification (Figure 4)
reveals that glioblastoma multiforme is the
most prevalent type of glioma seen in HIV-
1/AIDS patients (19/55), similar to what has
been reported for HIV-1 seronegative popula-
tions. In fact, all other types of gliomas, which
commonly affect seronegative patients, includ-
ing low grade astrocytomas and anaplastic
astrocytomas are minimally represented.
In conclusion, although there is compelling
evidence showing a direct role of protease
inhibitors as mediators of apoptosis and
inhibitors of angiogenesis in gliomas, further
epidemiological and basic science research
needs to be performed in controlled conditions
in order to elucidate if there are other factors
responsible for the protective anti-glioma
effect seen in HIV-1/AIDS patients.
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Review
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