Publisher: Karolinska Institutet, Microbiology and Tumor Biology Center (MTC)
Types: Doctoral thesis
Subjects: MEDICIN OCH HÄLSOVETENSKAP, biological phenotype, genetic subtype, chemokine receptor, coreceptor, mother- to-child transmission, placenta, disease progression, child, pregnancy, MEDICAL AND HEALTH SCIENCES
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With the global increase in human immunodeficiency virus 1 (HIV-1)
infection in women of childbearing age, there has also been an alarming
increase in the number of mother-to-child transmissions of HIV-1.
Although antiretroviral therapy and Cesarian section have been
demonstrated to significantly decrease the vertical transmission rate of
, these interventions are not widely available in the developing world.
Therefore, studies of the mechanisms of vertical transmission are
This thesis was based on a prospective follow-up of HIV-1-infected
patients, especially mothers and children in Sweden and in Cameroon.
Coreceptor usage of the primary HIV-1 isolates was determined on
indicator cell lines U87.CD4 and/or GHOST(3) engineered to express CD4
and one of the main chemokine receptors (CCR1, CCR2b, CCR3, CCR5, CXCR4,
Bob and Bonzo). The genetic subtype of the viruses was determined by
phylogenetic analysis of DNA sequences or by heteroduplex mobility assay
Coreceptor usage of 81 primary HIV-1 isolates was analysed in relation to
their biological phenotype, the genetic subtype and the severity of HIV-1
infection in adult patients. In all cases, tropism for MT-2 cells, a
previously used indicator cell line, correlated with CXCR4 usage.
Importantly, we found subtype-dependent differences in coreceptor usage,
in that dual tropic R5M viruses were detected less frequently among
subtype D isolates and that CXCR4 use was less frequent among subtype C
Coreceptor usage of primary HIV-1 isolates obtained from Cameroonian
pregnant women was also tested. HIV-1 mother-to-child transmission rate
was 11.9%. The majority of the virus isolates were of envelope subtype A
and used CCR5 as coreceptor for cell entry. Four isolates of 28 (14.2%)
were able to use the orphan receptor Bonzo as well. In two mothers (of
four tested) who transmitted HIV-1 to their children, virus with CCR5
Bonzo dual tropism emerged during pregnancy. Paired isolates from mother
and child were available in two cases and the coreceptor usage of these
pairs was concordant. Further analysis of available sequences from env
and pol showed that a majority of virus variants were recombinants
including subtype A. We found CRF02_AG(IbNG), a previously unrecognized
A/J recombinant and even more complex recombination patterns.
We studied HIV-1 infected mothers and their children living in Sweden,
where five genetic subtypes were represented. Regardless of genetic
subtype, HIV-1 isolated during pregnancy used in most cases CCR5.
Interestingly, all children carried virus of RS phenotype at the time of
HIV-1 diagnosis. However, in the children born to mothers that carried X4
virus a change in HIV-1 coreceptor use could be documented several months
later. The emergence of such viruses was preceeded by a drop in CD4 +T
cell counts and clinical progression in all patients.
To test the placental barrier function, we obtained ten term placentae
from a cohort of pregnant women in Sweden, identified as infected by
HIV-1 subtype A, B or C or HIV-2. All mothers underwent antiretroviral
therapy and all children were uninfected. HIV sequences were detected by
PCR in mother's PBMC and in enriched placental trophoblastic cell
preparations. After immunomagnetic cell separation of these mixed
populations, the purified trophoblasts were overall negative. Proviral
DNA was found in the non-trophoblastic placental cells, mainly
T-lymphocytes, which were shown to be a mixture of maternal and foetal.
cells. This study indicated that the placental barrier, Le., the
trophoblastic layer, was not HIV infected.
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