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 [phone](E-mail:[e-mail])
Abstract Results: Both patients were female, had lost one
parent >10yrs earlier but had the other surviving
parent exhibiting slow HIV disease progression. We
Background: Disease progression in human question the possible inheritance of the genetic
i m m u n o d e f i c i e n c y v i r u s / A c q u i r e d factors associated with slow disease progression in a
immunodeficiency syndrome (HIV/AIDS) is recessive X-linked Mendellian pattern and the role
affected by several factors both external and of the high prevalence of HIV within the sub-
internal to the human hosts. In the European Saharan setting as the selective pressure favoring
Caucasian populations, the chemokine-cell the establishment of the currently known
receptor variant CCR5 "Delta 32" is a the genetic immunologic and genetic factors influencing HIV
determinant of HIV disease progression that is diseases progression.
believed to have been selected for in the general Conclusion: A more in-depth immunologic and
population by exposure to antigens closely genetic approach is called for to further examine the
interlinked to HIV like Yersinia pestis or small pox baseline prevalence and possibility of adaptive
virus. Among African populations, it is possible that selection for immunogenetic protectors of HIV
this selection will be induced by HIV over time. disease progression within the sub-Saharan setting.
Aim: To present two cases of mother-to-child
transmitted HIV highlighting the possible
increasing prevalence of slow disease progression. Key words: Paediatric HIV, Slow progression,
Methods: Clinical case reports of slow progression Selective adaptation, Chance phenomenon
of pediatric HIV
Introduction transmitted (MTCT) HIV within the sub-Saharan
setting have been observed to die within 3-6 years
Human immunodeficiency virus (HIV) disease after birth if no highly active antiretroviral therapy
progression in humans is affected by a number of (HAART) is instituted, a number of discrepancies
factors, both exogenous and endogenous. Infants exist in this pattern of HIV disease progression. We
born with or who acquire HIV from their mothers present here two cases of MTCT HIV who were
form an ideal population for observing observed to survive into their late teens without
determinants of HIV disease progression in prior use of HAART as a succinct to further
humans. Within sub-Saharan Africa, poverty, examining the possible factors for slow progression
orphanage with its associated socio-economic of disease.
stresses and a high prevalence of opportunistic
infectious pathogens may be some of the
exogenous factors contributing to fast disease Case Reports
progression in infants who were born with, or
1,2
acquired HIV perinatally . Recent studies have Case 1
however identified and elucidated other
endogenous determinants of disease progression An 18-year-old girl was admitted in the later quarter
3-24
in HIV . While most cases of mother-to-child of 2002 via ward 4B to Intensive Care Unit (ICU),
Port Harcourt Medical Journal 2007 ; 2: 83-87 83

11-15 12-13
New Mulago Hospital (Uganda) with a diagnosis of other chemokine receptors CCR5 , CCR2 ,
16
HIV encephalopathy. Her sero-status (HIV +ve) and CX3CR1 , the chemokine-receptor ligands
17 18-20
had been known since age 7 years, both by Enzyme (CCL5-RANTES) , CCL2 (MCP1) , CCL3L1
21 22
Linked Immuno-absorbent Linked Assays (MIP1P) and CXCL12 (SDF-1) , the cytokine
23
(ELIZA) and Polymerase Chain Reaction (PCR). IL10 , a killer immunoglobulinreceptor(KIR) gene,
24
Her father had succumbed to acquired and APOBEC3G and HIV subtyping. We
immunodeficiency syndrome (AIDS) in 1992 (10 assumed that the surviving parent had acquired
years preceding this admission). The mother was HIV infection from the late partner, although this
HIV +ve, not on antiretroviral therapy (ART), and was unreliable history, especially given the
yet well and alive (10 to 18 years following discordance that assails primary HIV infection
presumed contraction). ART was only initiated in among a section of married couples with a history
this case after discussing the prognosis with the of unprotected extramarital sexual intercourse.
mother. The past medical history indicated These two cases serve to illustrate the fact that
previous repeated upper respiratory tract infections although most cases of mother-to-child
(URTI), but this was the first major hospitalization. transmitted (MTCT) human immunodeficiency
The CD4 cell counts was 180cells/µL but the viral virus (HIV) succumb to AIDS-related illnesses
loads were not done. within 3-6 years after birth, of late, some
discrepancy in disease progression have been
observed occur and some patients survive into the
Case 2 late teens despite not being on highly active
antiretroviral therapy. The question this raises is
A 16 year old girl was admitted in coma with whether this progression is a matter of chance, a
polyneuritis and hemiparesis to Ward 4B, Mulago consequence of a more health friendly exogenous
Hospital Uganda between March and April 2004. environment or there is an on-going selective
Toxoplasmosis was suspected on admission. Along adaptation for the endogenous factors that
the way, the diagnosis was changed from central determine HIV disease progression within the sub-
nervous system (CNS) toxoplasmosis to possible Saharan setting as has been noted elsewhere
tuberculous meningitis following a negative serum Interaction with clinicians at various paediatric HIV
and cerebral spinal fluid (CSF) screen for toxo- treatment centres in Uganda such as Mild May,
titres, and a highly marked CSF lymphocytosis, Entebbe Road, Joint Clinical Research Centre
turbid CSF despite a negative Ziehl-Neelsen (ZN) (JCRC), Mango, The AIDS Support Organization
stain for acid fast bacilli (AFB). CD4 cell counts (TASO), Mulago, and the Paediatric Infectious
were110cells/µL but the viral loads were not done. Disease Clinic(PIDC), Makerere, offered
She was HIV +ve, her mother had died with AIDS undocumented support to our observations.
10 years previously, but the father was alive. He too
For instance, individuals who are homozygous
was HIV +ve but had not progressed to AIDS,
for a 32-bp deletionin the chemokine-cell receptor
presumably 10-16 years after contraction despite
gene (CCR5) are highly resistant to infection by
not being on HAART. 3,4
HIV-1 . This CCR5 "Delta 32" variant became
established in Europe centuriesago, perhaps under
selective pressure from some other pathogen such
Discussion 5 6
as Yersinia pestis or smallpox . Because of non-
permissive conditions, it was not possible to do
In both cases, facilities were not readily available to gentotyping for the CCR5 "Delta 32" variant, as
conduct histo-immuno-genetic assays for some of well as a full bacteriology and virology screen to rule
the factors associated with slow progression of out previous infections with such pathogens in
HIV disease such as chemokine-cell receptor gene both cases presented. However, our observation
11-15
(CCR5) variant "Delta 32 [ CCR5 "Delta 32"] , underlines the need to search for the possibility of
7-10
histocompatibility complex (MHC) genotype , such endemic pathogens within the sub-Saharan
5,6.
Slow progression of paediatric HIV M. Wayengera
Port Harcourt Medical Journal 2007 ; 2: 83-87 84

setting that may select for such protective Additional human genetic variants reported to
endogenous factors. It is also likely that the influence HIV-1 transmission, viral replication,
selection in this setting for this variant will occur and/or disease progression include those of the
7-10
under the pressure of HIV itself, given that over major histocompatibility complex(MHC) genes ,
70% of cases of HIV occur here as per The Joint aswell as other variants,in the chemokine receptors
11-15 12-13 16
U n i t e d N a t i o n s P r o g r a m m e o n CCR5 , CCR2 , and CX3CR1 , the
17
HIV/AIDSIUNAIDS) progress reports over 1999 chemokine-receptor ligands CCL5-RANTES ,
25 17-19 20
to 2006 . It is worth noting the slow progression CCL2 (MCP1) , CCL3L1 (MIP1P) , and
21 22
history of HIV disease in the surviving biological CXCL12 (SDF-1) , the cytokine IL10 , a killer
23
parent of both cases . Case 1 had a mother who was immunoglobulinreceptor (KIR) gene , and
24
HIV+ve but well and not yet on HAART about 18 APOBEC3G . Just as HIV evolves within the
years after presumed contraction (provided her human body to escape selective pressure from
current HIV strain was acquired from the late MHC genes, the human genome is also under
father). Similarly, case 2 had a surviving father who selective pressure from microbes. In sub-Saharan
was HIV+ve but well and not yet on HAART Africa, where HIVis highly endemic, geneticfactors
about 16 years after presumed contraction. It was that delay HIV disease progression such as certain
also interesting to note that both patients reported human leucocytes antigen (HLA) types will likely
were females. These additional observations have become somewhat enriched in the population,
led us to question, if an endogenous protective whereas those which promote rapid progression to
factor was involved, if or not this factor is AIDS will decline.
genetically transmitted through a sex-linked
Mendellian style inheritance (X-linked recessive
trait expressed in the heterozygous form in Conclusion
females).
setting that may select for such protective A more in-depth immunologic and genetic
endogenous factors. It is also likely that the approach is called for to establish the current
selection in this setting for this variant will occur baseline prevalence and to further examine the
under the pressure of HIV itself, given that over possibility of adaptive selection for immunologic
70% of cases of HIV occur here as per The Joint protectors of HIV disease progression within the
U n i t e d N a t i o n s P r o g r a m m e o n sub-Saharan setting.
HIV/AIDSIUNAIDS) progress reports over 1999
25
to 2006 . It is worth noting the slow progression
history of HIV disease in the surviving biological Competing interests: none
parent of both cases . Case 1 had a mother who was
HIV+ve but well and not yet on HAART about 18 Funding: The author received no specific funding
years after presumed contraction (provided her towards this study
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 References
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).
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Port Harcourt Medical Journal 2007 ; 2: 83-87 87