Chronic immune activation associated with chronic helminthic and human immunodeficiency virus infections: role of hyporesponsiveness and anergy

Abstract

Chronic immune activation is one of the hallmarks of human immunodeficiency virus (HIV) infection. It is present also, with very similar characteristics, in very large human populations infested with helminthic infections. We have tried to review the studies addressing the changes in the immune profiles and responses of hosts infected with either one of these two chronic infections. Not surprisingly, several of the immune derangements and impairments seen in HIV infection, and considered by many to be the "specific" effects of HIV, can be found in helminth-infected but HIV-noninfected individuals and can thus be accounted for by the chronic immune activation itself. A less appreciated element in chronic immune activation is the immune suppression and anergy which it may generate. Both HIV and helminth infections represent this aspect in a very wide and illustrative way. Different degrees of anergy and immune hyporesponsiveness are present in these infections and probably have far-reaching effects on the ability of the host to cope with these and other infections. Furthermore, they may have important practical implications, especially with regard to protective vaccinations against AIDS, for populations chronically infected with helminths and therefore widely anergic. The current knowledge of the mechanisms responsible for the generation of anergy by chronic immune activation is thoroughly reviewed.

FIG. 1.

Distribution of helminths and HIV-1 in Africa. The prevalence of infection by helminths and HIV-1 is based on data obtained from references and for helminths and reference for HIV.

FIG. 2.

Decreased immune activation following deworming. The effect of helminth eradication on the immune system was studied by following up several immunological markers in two subgroups of the Ethiopian immigrants to Israel. The treated group included 30 individuals infested with one or more helminthic parasites. Blood samples were taken from them before and 6 to 12 months after eradication of the parasites. The untreated group included 19 new Ethiopian immigrants to Israel, who lived in the same environment as the treated group but did not receive anthelminthic treatment and remained infested with helminths during the whole study period. The graphs show the percent relative changes (PRC) of immunological parameters between two consecutive blood tests (X₁ and X₂) taken 6 to 12 months apart. The PRC was calculated as follows: PRC = [(X₂ − X₁)/X₁] × 100. Each bar represents the PRC mean ± standard error for each group. The significance of the difference between the PRC (P value), determined by the Mann-Whitney rank test, is shown.

FIG. 3.

T-cell hyporesponsiveness during chronic immune activation. The chart represents different features altered during chronic immune activation caused by persistent HIV-1 or helminthic infection. Representative factors found to be altered are depicted. Chronic immune activation causes (i) an increase in the level of CTLA-4, which downregulates T-cell responses by raising the threshold for effective T-cell activation (CTLA-4 engagement also leads to expression of the downregulatory cytokine TGF-β); (ii) downregulation of CD28 (effective stimulation of T cells via the TCR requires costimulatory signaling through the ligation of CD28 receptor with CD80 or CD86 ligands of APC; TCR stimulation in the absence of CD28-mediated costimulation induces a long-lasting hyporesponsive state); (iii) a reduction in CD80 in APC, which decreases the effective stimulation of T cells; (iv) an increase in constitutive levels of intracellular negative regulators, such as Cbl-b; (v) impaired cytoplasmatic signal transduction, such as decreased phosphorylation of ERK 1/2; (vi) decreased translocation to the nucleus and activation of transcription factors, such as NF-κB; and (vii) an increase in the number of Treg cells, which induce T-cell hyporesponsiveness directly by cell contact and through downregulatory cytokines such as IL-10 and TGF-β. The TH2 skewed immune profile associated with HIV-1 and helminthic infections results in upregulation of downregulatory cytokines and probably of Treg cells. In addition, soluble factors originating from HIV or helminthic parasites, such as gp120 and ES-62, interact with the T cells, augmenting cellular impairments and hyporesponsiveness.

FIG. 4.

Increased levels of CTLA-4 and Cbl-b and attenuated phosphorylation of ERK-1/2 in immune-activated HIV-1 or helminth-infected individuals. PBMC were obtained from HIV-seronegative [HIV(−)], HIV⁺ [HIV(+)], Ethiopian immigrants to Israel (ETH) noninfected [Hel(−)], and ETH helminth-infected [Hel(+)] individuals. Lysates from the nonstimulated PBMC (−) or from PBMC stimulated with 0.5 μg of anti-CD3 monoclonal antibody for 5 min (+) were resolved on by sodium dodecyl sulfate-polyacylamide gel electrophoresis and immunoblotted with anti-BCL2, anti-phosphorylated p42/44 MAPK/ERK, anti-Cbl-b, or anti-CTLA-4 antibodies. In addition, the percent surface HLA-DR expression and intracellular pools of CTLA-4 were determined by flow cytometry.

FIG. 5.

Possible interference of helminthic and/or HIV-1 infections on the capacity of the host to mount immune responses to exogenous antigens or agents. Infection with helminthic parasites and HIV-1 induce (i) an increase in the threshold for effective immune stimulation (e.g., upregulation in CTLA-4), (ii) a defective intracellular signaling (e.g., phosphorylation and dephosphorylation of kinases), (iii) a decrease in the number of costimulatory molecules necessary for effective antigen presentation (e.g., CD28), (iv) an increase in the number of T-regulatory/inhibitory cells, (v) an increase in the levels of negative regulators of T-cell activation (e.g., Cbl-b), (vi) an increase in the levels of downregulatory cytokines (e.g., TGF-β), and (vii) an imbalance in the proportion of T cells (e.g., a decrease in the relative number of CD4⁺ cells). All of these changes contribute to hyporesponsiveness and anergy of the immune system. Coinfection with helminths and HIV-1 exacerbates this process and may also result in accelerated progression to AIDS.