| Abstract |
BACKGROUND: More than 25 years have passed since the emergence of the
HIV-1 epidemic. During this time our knowledge about the pathogenesis of HIV-1
infection has increased substantially achieving many accomplishments in its
prevention and medical treatment. A critical step has been the introduction of HAART
(Highly Active Antiretroviral Therapy) which has significantly prolonged the survival
of infected patients. However HAART does not cure the infection and new targets for
therapy are being pursued.
The chemokine network is a promising field of research. It consists of
receptors and molecules produced by tissue cells at sites of inflammation and
leucocytes. Its role is to mediate the creation of immune responses. However HIV-1
exploits the chemokine network and uses its receptors for cell adhesion and infection.
The receptors CXCR4 and CCR5 are used by HIV-1 to enter lymphocytes and
macrophages. The mutation CCR5Δ32 leads to a truncated form of CCR5 which does
not appear on the cell surface conferring infection immunity to homozygous
individuals and resistance to infection progression in heterozygous patients. This has
resulted in the creation of CCR5 antagonists for use in HIV-1 medical treatment.
Other mutations in chemokine receptors or their ligands have also been shown to
affect the progression of HIV-1 infection.
OBJECTIVE: In this study we examined the effects of nine chemokine
polymorphisms on immunologic and virologic response to HAART in a group of 149
patients followed in “A. Syngros” Hospital (Athens). The polymorphisms were
CCR5Δ32, CXCL12-3A, CCR2-64I, CCR5-59029G/A, CXCR6-3E/K, In1.1T/C, H7
haplotype, CX3CR1-V249I and CX3CR1-T280M.
STUDY DESIGN: We genotyped our patients using PCR and agarose and
acrylamid gel electrophoresis. We performed Kaplan-Meier analysis using the
following end-point criteria: 1) time from HAART initiation to undetectable viral load
(VL<50 copies/ml),(2) maximum duration of viral suppression, (3) time from
HAART administration until CD4 elevation ≥200 cells/mm3 for patients with baseline
CD4 below 200 cells/mm3 and ≥500 cells/mm3 for patients with baseline CD4
between 200 and 499 cells/mm3, respectively, and (4) time from HAART initiation
until CD4 reduction below baseline values.
RESULTS: Our results revealed that patients with baseline CD4 between 200-
499 cells/mm3 and heterozygous or homozygous for the CCR2-64I allele achieved
undetectable VL counts at 3.5±0.5 months as compared to 10.2±1.4 months in the
group homozygous for the wild type receptor CCR2 (p =0.018, n=69). Additionally
patients with CCR2-64I retained undetectable VL for 28±2 months in contrast to 20±2
months in the homozygous wild type group (p =0.048, n=69). Patients with baseline
CD4 between 200-499 cells/mm3 carrying CXCL12-3A restored the CD4 population
faster than the homozygous wild type group (mean: 9±2 and 14±2 months,
respectively, p =0.023, n=69) and demonstrated a trend for faster VL suppression than
the wild type group (7.4±1.6 months and 10.5±1.7 months respectively, p=0.103,
n=69). Patients with the CXCR6-3K in homozygous or eterozygous state exhibited a
shorter duration of viral suppression (<50cps/ml) in comparison to homozygous
CXCR6-3E patients (mean 19±6 and 48±3 months respectively, p=0.036, n=137). On
the other hand the CX3CR1-249I and CX3CR1-280M alleles in homozygous states
were correlated with a favourable response to HAART by faster restoration of CD4
counts to higher levels compared to the homozygous CX3CR1-249V and CX3CR1-
280T states respectively (mean: 3±1 months in CX3CR1-249I/I patients, 16±2 months
in CX3CR1-249V/V patients, p =0.001, n =115 and mean 3±2 months in CX3CR1-
280M/M patients and 19±3 months in CX3CR1-280T/T patients, p =0.024, n =115).
CONCLUSION: The polymorphisms CCR2-64I, CXCL12-3A, CXCR6-3E/K,
CX3CR1-V249I and CX3CR1-T280M affect the immunological and virological
response to the initiation of HAART in HIV-1 infected patients. The results from this
study suggest that the above chemokines and receptors are important in the
pathogenesis of HIV-1 infection and may provide new targets for therapy in the future
after better understanding of their interactions.
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