Coreceptor expression and T lymphocyte subset distribution in HIV-infected and TB co-infected South African patients on anti-retroviral therapy

[摘要] ENGLISH ABSTRACT: In 2007, AIDS caused an estimated 2.1 millions deaths worldwide; about 70% in sub-SaharanAfrica. HIV preferentially targets activated CD4 T cells, expressing the major HIV receptorCD4, as well as the major chemokine coreceptors CCR5 and CXCR4. These coreceptors playa prominent role during HIV cell entrance phase, HIV transmission and also diseaseprogression. They have been found to be differentially expressed by CD4 T cell subsets.Tuberculosis coinfection may enhance immune activation in vivo thus accelerating HIVdisease progression and has become a major challenge in the control of TB in Africa.Introduction of HAART has reduced disease progression to AIDS, as well as risk of furthermorbidity and mortality. HAART results in a rapid decline of viral load and an initial increaseof peripheral CD4 count, however little is known on the effect of HAART in regulation ofcoreceptor expression, immune activation status and CD4 T cell subset distribution in HIVinfection and HIV/TB coinfection.This study is a cross-sectional analysis of coreceptor expression, immune activation status andCD4 T cell subpopulation distribution in South African HIV and HIV/TB coinfected patientsbefore and after ARV. A total of 137 South African individuals were investigated, comprising15 healthy normal donors (healthy subgroup), 10 patients with active pulmonary tuberculosis(PTB subgroup), 33 HIV-1 positive patients without active PTB (HIV subgroup), 23 positivepatients with active PTB (HIV/PTB subgroup), 36 HIV-1 positive patients on ARV (HIV onARV subgroup) and 20 HIV-1 positive patients with active PTB on ARV (HIV/PTB on ARVsubgroup).CD4 absolute count and plasma viral load were determined for all donors. Freshly isolatedPBMC were classified by flow cytometry into the following CD4+ T lymphocyte subsets:naïve (CD45+, CD27+), effector memory (CD45-, CD27-), central memory (CD45-, CD27+),and effector (CD45+, CD27-). Coreceptor expression and activation status was assessed byCCR5, CXCR4 and CD38 expression on CD4 T cell subsets.HIV, TB and HIV/TB coinfection was associated with a decrease in percentage CCR5+ Tcells as compared to healthy controls, with the HIV/TB group showing the most extensivedecrease. In treatment naive patients, CD4 T cells showed elevated surface expression ofCCR5 and CD38 as determined by mean fluorescence intensity in HIV/TB co-infectioncompared to HIV infection alone. The percentage of antigen-experienced cells was higher inthe HIV/TB co-infected group compared to the HIV group. The percentage of naïve T cellswas decreased in both the HIV infected and the HIV/TB co-infected groups compared tohealthy controls. HIV patients with more than 6 months of ARV showed decreased CCR5 andCD38 surface level expression in the HIV and the HIV/ TB co-infected subgroups. Anincreased percentage of naïve T cells was observed in the HIV infected subgroup, but not inthe HIV/TB subgroup, similarly, a decreased percentage of antigen-experienced cells wasobserved in the HIV subgroup, but not in the HIV/TB co-infected subgroup. A positivecorrelation was found between CCR5 and CD38 expression, and CXCR4 and CD38expression (Spearman coefficient of correlation respectively: r=0.59, p<0.001 and r=0.55,p<0.001). Furthermore we found plasma viral load positively associated with CD38expression (r=0.31, p<0.001) and percentage activated CCR5+ expressing CD4 T cellspositively related to viral load (r=0.31, p<0.001). Percentage naïve CD4 T cells was positivelyassociated with CD4 count (r=0.60, p<0.001) and negatively correlated to viral load (r=-0.42,p<0.001).These results indicate that TB coinfection exacerbates certain aspects of dysregulation of CD4T cell homeostasis and activation caused by HIV infection. In addition, ARV-associateddecrease in coreceptor expression, immune activation status and a normalisation of CD4 Tcell subset distribution was observed in HIV infected individuals, but not in HIV/TB coinfection.Despite viral suppression after ARV treatment, the decline in the immune activationmarker CD38 and coreceptor CCR5 expression, increase in percentage naïve CD4 T cells anddecrease of antigen-experienced cells did not reach the levels displayed in the healthy controlgroup. This may indicate that ongoing (albeit reduced) T cell immune activation may occur inthe presence of ARV. Further longitudinal studies are needed to closely monitor immuneactivation during ARV treatment.This study highlighted an association of TB disease with immune activation in HIV infection,the importance of T-cell activation in HIV pathogenesis and its impact on ARV treatment.Further studies are needed to identify causative factors that may lead to a persistent immuneactivation status during ARV treatment, and how TB coinfection confounds normal responsesto ARV.

[发布机构] Stellenbosch University