Effects and mechanisms of interleukin-10 Promoter Polymorphisms in HIV-1 Susceptibility and pathogenesis

Dshanta Dyanedi Naicker, Thumbi Ndung'u

Abstract


The interleukin-10 (IL-10) proximal promoter region contains 2 biallelic

polymorphisms at positions -1082 (A to G transition) and -592 (C to A transversion),

which are related to levels of IL-10 production. Polymorphisms associated with

decreased IL-10 production have been associated with an increased likelihood of

human immunodeficiency virus type 1 (HIV-1) acquisition and an accelerated rate of

CD4+ T cell decline, particularly in late-stage disease, suggesting that high IL-10

production may reduce susceptibility to HIV-1 infection and protect against disease

progression. Paradoxically, 2 recent studies of lymphocytic choriomeningitis virus

(LCMV) in mice, a model of chronic viral infections, have demonstrated that removal

of IL-10 or blockade of the IL-10 pathway may enhance T cell immune responses,

resulting in the rapid elimination of virus and the development of antiviral memory T

cell responses and culminating in LCMV clearance. The effect of IL-10 on HIV-1

replication in vivo is further complicated by the observation that the cytokine directly

inhibits HIV-1 replication in human macrophages. The inhibitory effects of IL-10 on

HIV-1 replication may become more pronounced in late stages of disease, when

CD4+ lymphocytes are depleted and replication in macrophages and monocytes

predominates. Recent data from my Masters research showed that polymorphisms

associated with higher IL-10 production were associated with decreased susceptibility

to infection but an increased peak viral load during acute infection, a difference that

subsequently disappeared.