Slow_progression.pdf

Slow progression of paediatric HIV disease: Selective
adaptation or a chance phenomenon?
M. Wayengera
Faculty of Medicine, Makerere University, P O Box 7072, Kampala, Uganda
Correspondence to: Dr. Wayengera Misaki, 4001 Steeles Ave West, Suite 1203. North York, TO, ON.
Canada. M3N2T8. Tel 1 647 409 1979(E-mail:[email protected])
Abstract
Background: Disease progression in human
immunodeficiency virus/Acquired
immunodeficiency syndrome (HIV/AIDS) is
affected by several factors both external and
internal to the human hosts. In the European
Caucasian populations, the chemokine-cell
receptor variant CCR5 "Delta 32" is a the genetic
determinant of HIV disease progression that is
believed to have been selected for in the general
population by exposure to antigens closely
interlinked to HIV like Yersinia pestis or small pox
virus. Among African populations, it is possible that
this selection will be induced by HIV over time.
Aim: To present two cases of mother-to-child
transmitted HIV highlighting the possible
increasing prevalence of slow disease progression.
Methods: Clinical case reports of slow progression
of pediatric HIV
Introduction
Human immunodeficiency virus (HIV) disease
progression in humans is affected by a number of
factors, both exogenous and endogenous. Infants
born with or who acquire HIV from their mothers
form an ideal population for observing
determinants of HIV disease progression in
humans. Within sub-Saharan Africa, poverty,
orphanage with its associated socio-economic
stresses and a high prevalence of opportunistic
infectious pathogens may be some of the
exogenous factors contributing to fast disease
progression in infants who were born with, or
1,2
acquired HIV perinatally . Recent studies have
however identified and elucidated other
endogenous determinants of disease progression
in HIV 3-24. While most cases of mother-to-child
Port Harcourt Medical Journal 2007 ; 2: 83-87
Results: Both patients were female, had lost one
parent >10yrs earlier but had the other surviving
parent exhibiting slow HIV disease progression. We
question the possible inheritance of the genetic
factors associated with slow disease progression in a
recessive X-linked Mendellian pattern and the role
of the high prevalence of HIV within the subSaharan setting as the selective pressure favoring
the establishment of the currently known
immunologic and genetic factors influencing HIV
diseases progression.
Conclusion: A more in-depth immunologic and
genetic approach is called for to further examine the
baseline prevalence and possibility of adaptive
selection for immunogenetic protectors of HIV
disease progression within the sub-Saharan setting.
Key words: Paediatric HIV, Slow progression,
Selective adaptation, Chance phenomenon
transmitted (MTCT) HIV within the sub-Saharan
setting have been observed to die within 3-6 years
after birth if no highly active antiretroviral therapy
(HAART) is instituted, a number of discrepancies
exist in this pattern of HIV disease progression. We
present here two cases of MTCT HIV who were
observed to survive into their late teens without
prior use of HAART as a succinct to further
examining the possible factors for slow progression
of disease.
Case Reports
Case 1
An 18-year-old girl was admitted in the later quarter
of 2002 via ward 4B to Intensive Care Unit (ICU),
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Slow progression of paediatric HIV
New Mulago Hospital (Uganda) with a diagnosis of
HIV encephalopathy. Her sero-status (HIV +ve)
had been known since age 7 years, both by Enzyme
Linked Immuno-absorbent Linked Assays
(ELIZA) and Polymerase Chain Reaction (PCR).
Her father had succumbed to acquired
immunodeficiency syndrome (AIDS) in 1992 (10
years preceding this admission). The mother was
HIV +ve, not on antiretroviral therapy (ART), and
yet well and alive (10 to 18 years following
presumed contraction). ART was only initiated in
this case after discussing the prognosis with the
mother. The past medical history indicated
previous repeated upper respiratory tract infections
(URTI), but this was the first major hospitalization.
The CD4 cell counts was 180cells/µL but the viral
loads were not done.
Case 2
A 16 year old girl was admitted in coma with
polyneuritis and hemiparesis to Ward 4B, Mulago
Hospital Uganda between March and April 2004.
Toxoplasmosis was suspected on admission. Along
the way, the diagnosis was changed from central
nervous system (CNS) toxoplasmosis to possible
tuberculous meningitis following a negative serum
and cerebral spinal fluid (CSF) screen for toxotitres, and a highly marked CSF lymphocytosis,
turbid CSF despite a negative Ziehl-Neelsen (ZN)
stain for acid fast bacilli (AFB). CD4 cell counts
were110cells/µL but the viral loads were not done.
She was HIV +ve, her mother had died with AIDS
10 years previously, but the father was alive. He too
was HIV +ve but had not progressed to AIDS,
presumably 10-16 years after contraction despite
not being on HAART.
Discussion
In both cases, facilities were not readily available to
conduct histo-immuno-genetic assays for some of
the factors associated with slow progression of
HIV disease such as chemokine-cell receptor gene
(CCR5) variant "Delta 32 [ CCR5 "Delta 32"] 11-15,
7-10
histocompatibility complex (MHC) genotype ,
Port Harcourt Medical Journal 2007 ; 2: 83-87
M. Wayengera
, CCR2 12-13,
and CX3CR1 , the chemokine-receptor ligands
(CCL5-RANTES) 17, CCL2 (MCP1) 18-20, CCL3L1
(MIP1P) 21 and CXCL12 (SDF-1) 22, the cytokine
IL10 23, a killer immunoglobulinreceptor(KIR) gene,
and APOBEC3G 24 and HIV subtyping. We
assumed that the surviving parent had acquired
HIV infection from the late partner, although this
was unreliable history, especially given the
discordance that assails primary HIV infection
among a section of married couples with a history
of unprotected extramarital sexual intercourse.
These two cases serve to illustrate the fact that
although most cases of mother-to-child
transmitted (MTCT) human immunodeficiency
virus (HIV) succumb to AIDS-related illnesses
within 3-6 years after birth, of late, some
discrepancy in disease progression have been
observed occur and some patients survive into the
late teens despite not being on highly active
antiretroviral therapy. The question this raises is
whether this progression is a matter of chance, a
consequence of a more health friendly exogenous
environment or there is an on-going selective
adaptation for the endogenous factors that
determine HIV disease progression within the sub5,6
Saharan setting as has been noted elsewhere .
Interaction with clinicians at various paediatric HIV
treatment centres in Uganda such as Mild May,
Entebbe Road, Joint Clinical Research Centre
(JCRC), Mango, The AIDS Support Organization
(TASO), Mulago, and the Paediatric Infectious
Disease Clinic(PIDC), Makerere, offered
undocumented support to our observations.
For instance, individuals who are homozygous
for a 32-bp deletion in the chemokine-cell receptor
gene (CCR5) are highly resistant to infection by
3,4
HIV-1 . This CCR5 "Delta 32" variant became
established in Europe centuries ago, perhaps under
selective pressure from some other pathogen such
5
6
as Yersinia pestis or smallpox . Because of nonpermissive conditions, it was not possible to do
gentotyping for the CCR5 "Delta 32" variant, as
well as a full bacteriology and virology screen to rule
out previous infections with such pathogens in
both cases presented. However, our observation
underlines the need to search for the possibility of
such endemic pathogens within the sub-Saharan
other chemokine receptors CCR5
11-15
16
84
Slow progression of paediatric HIV
setting that may select for such protective
endogenous factors. It is also likely that the
selection in this setting for this variant will occur
under the pressure of HIV itself, given that over
70% of cases of HIV occur here as per The Joint
United Nations Programme on
HIV/AIDSIUNAIDS) progress reports over 1999
to 2006 25. It is worth noting the slow progression
history of HIV disease in the surviving biological
parent of both cases . Case 1 had a mother who was
HIV+ve but well and not yet on HAART about 18
years after presumed contraction (provided her
current HIV strain was acquired from the late
father). Similarly, case 2 had a surviving father who
was HIV+ve but well and not yet on HAART
about 16 years after presumed contraction. It was
also interesting to note that both patients reported
were females. These additional observations have
led us to question, if an endogenous protective
factor was involved, if or not this factor is
genetically transmitted through a sex-linked
Mendellian style inheritance (X-linked recessive
trait expressed in the heterozygous form in
females).
setting that may select for such protective
endogenous factors. It is also likely that the
selection in this setting for this variant will occur
under the pressure of HIV itself, given that over
70% of cases of HIV occur here as per The Joint
United Nations Programme on
HIV/AIDSIUNAIDS) progress reports over 1999
25
to 2006 . It is worth noting the slow progression
history of HIV disease in the surviving biological
parent of both cases . Case 1 had a mother who was
HIV+ve but well and not yet on HAART about 18
years after presumed contraction (provided her
current HIV strain was acquired from the late
father). Similarly, case 2 had surviving a father who
was HIV+ve but well and not yet on HAART
about 16 years after presumed contraction. It was
also interesting to note that both patients reported
were females. These additional observations have
led us to question, if an endogenous protective
factor was involved, if or not this factor is
genetically transmitted through a sex-linked
Mendellian style inheritance (X-linked recessive
trait expressed in the heterozygous form in
females).
Port Harcourt Medical Journal 2007 ; 2: 83-87
M. Wayengera
Additional human genetic variants reported to
influence HIV-1 transmission, viral replication,
and/or disease progression include those of the
7-10
major histocompatibility complex (MHC) genes ,
as well as other variants, in the chemokine receptors
11-15
12-13
16
CCR5
, CCR2
, and CX3CR1 , the
chemokine-receptor ligands CCL5-RANTES17 ,
CCL2 (MCP1) 17-19, CCL3L1 (MIP1P) 20, and
CXCL12 (SDF-1)21, the cytokine IL10 22, a killer
23
immunoglobulinreceptor (KIR) gene , and
24
APOBEC3G . Just as HIV evolves within the
human body to escape selective pressure from
MHC genes, the human genome is also under
selective pressure from microbes. In sub-Saharan
Africa, where HIVis highly endemic, geneticfactors
that delay HIV disease progression such as certain
human leucocytes antigen (HLA) types will likely
become somewhat enriched in the population,
whereas those which promote rapid progression to
AIDS will decline.
Conclusion
A more in-depth immunologic and genetic
approach is called for to establish the current
baseline prevalence and to further examine the
possibility of adaptive selection for immunologic
protectors of HIV disease progression within the
sub-Saharan setting.
Competing interests: none
Funding: The author received no specific funding
towards this study
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