Phenotypic and functional characterization of cytotoxic T lymphocytes in HIV-1 infected South African adults

[摘要] ENGLISH ABSTRACT: In just 25 years since the first reported cases in 1981, the number of HumanImmunodeficiency virus (HIV) infected people has risen to 65 million, and over 25million have died of acquired immunodeficiency syndrome (AIDS). Sub-Saharan Africaaccounts for 67% of all people living with HIV and 72% of deaths in this region wereAIDS related. Tuberculosis (TB) is one of the most common opportunistic infections inAIDS patients, particularly in developing countries, where 60 - 70% of TB cases occurin HIV-1-infected persons. HIV-1 is a high risk factor for the development of TB, thereactivation of a latent Mycobacterium tuberculosis infection and also progressive TB.CD8+ Cytotoxic T Lymphocytes (CTL) are pivotal in the host immune response to HIVinfection. CTL are associated with resolution of acute infection and with reduction inviral load. Studies in macaques and humans indicate the importance of CTL in thecontrol of HIV infection, where reduction in CD8+ T cell number has been correlatedwith progression to AIDS.The current study was a cross-sectional descriptive study of CD8+ T cells of HIV+ adultSouth Africans with and without TB co-infection (TB disease). The cohort consisted ofanti-retroviral therapy (ART) naive patients and all CTL analyses were carried out onperipheral blood mononuclear cells (PBMCs). A total of 60 South African adults from theWestern Cape were utilized in this study, including 15 healthy controls; 30 HIV+TB-individualsand 15 HIV+TB+ individuals. Expression of phenotypic, activation andfunctional markers were investigated by flow cytometry with the use of fluorochomeconjugatedantibodies. The markers examined included the novel activation markerCD137, the CTL associated markers Perforin, Granzyme A, CD107a/b, Fas (CD95),and FasL (CD95L), intracellular cytokines IFN-y and TNF-a and the chronic HIV CTLdysfunction marker PD-1.HIV infection alone was associated with increased baseline expression of TNF-a,Perforin, Granzyme A, PD-1, Fas (CD95), and FasL (CD95L), but not CD137(4-1BB) orIFN-y as compared to uninfected controls. TB co-infection resulted in further increasedbaseline expression of TNF-a, perforin, PD-1, FasL (CD95L), as well as increased IFN-y. HIV-1 antigen (gag)-specific stimulation in vitro indicated that in HIV infection wasassociated with antigen-specific upregulation of activation and cytotoxicity markersCD137, IFN-y, TNF-a, Fas, FasL and CD107a/b. In TB co-infection a reduction inantigen-specific degranulation (CD107a/b up-regulation) and also Fas and FasLexpression was observed.TB co-infection (in the form of active pulmonary TB) reduced antigen-specific CTLfunctional activity, but simultaneously there was an association with increased baselinePD-1 expression and also cytolytic marker expression (Fas, FasL, TNF-a). Thesecytolytic markers could be involved in non-antigen-specific bystander target cell death.The expression of the co-stimulatory molecule CD137 appeared to correlate withinterferon-y production and levels of degranulation, confirming its usefulness as aputative surrogate marker of functional responsiveness. These data indicate that inaddition to impacting on CD4 T cell function, TB co-infection leads to higher baselineexpression of CTL-associated markers, but to dysfunctional antigen-specific CTLresponses.

[发布机构] Stellenbosch University