High Incidence of Pulmonary Tuberculosis in ART Naive Remunerated Blood Donors with Human Immunodeficiency Virus Type-1 Infection: Possible Role of Iron Overload

Iron overload is reported to be associated with immune alterations and increased susceptibility to infections. HIV infection is characterized by progressive immunodeficiency leading to invasion by opportunistic pathogens. It was of interest to find out if disease course in HIV type-1 infection could have any relation with alteration in body iron status among individuals with history of oral iron intake. A follow-up study of immunologic and virologic markers in relation to disease progression was undertaken on asymptomatic HIV-1 positive blood donors with history of oral iron intake (subgroup I) compared to those without such history (subgroup II). High serum iron was associated with elevated levels of Th2 category of cytokines, heightened immune activation, faster decline in CD4 + T lymphocyte count and higher viral set point. Pulmonary tuberculosis (PT) was the most common AIDS related illness (ARI) (>70%) recorded among subgroup I compared to non-PT category of ARI. Median ARI free duration (months) was shorter among those who developed PT compared to those developing non-PT category of ARI i.e. 30 (95% CI as 26,32) versus 67(95% CI as 60,71) in subgroup I and 47 (95% CI as 42,49) versus 80 (95% CI as 72,87) in subgroup II (P P < 0.001 for PT versus non-PT in both subgroups). The present study indicates that body iron overload resulting from excess intake of iron may be associated with qualitative defects in cell mediated immunity at early stage of HIV-1 infection that may facilitate subsequent acquisition of pulmonary tuberculosis, shorter ARI free duration and reduced survival.

Impaired <i>in Vitro</i>Macrophage Function in HIV-1 Infected Remunerated Blood Donors with History of Oral Iron Intake

Both HIV-1 infection and iron overload are independently associated with infection by Mycobacterium tuberculosis due to impaired macrophage function. A prospective study of in vitro assessment of macrophage function was undertaken in a group of asymptomatic HIV-1 infected remunerated (professional) blood donors with (n = 54) or without (n = 54) prevalent practice of oral iron intake (subgroups I and II respectively). The assessment was carried out at enrolment as well as at the point of development of AIDS related illness (ARI). The subgroup I showed higher levels of pro-inflammatory cytokines viz. IL-1β, IL-6 and IL-8, but lowered levels of IL-12p70 in serum as well as in supernatant of monocyte derived macrophage (MDM) cultures both at enrolment and at the point of development of ARI in the subset of cases that developed pulmonary tuberculosis (PT) on follow up compared to the subset that developed categories of ARI other than pulmonary tuberculosis (non-PT) on follow up. The subgroup II of HIV-1 positive donors did not show any such alterations at enrolment or at the point of development of PT or non-PT categories of ARI on follow up. There was significant depression of nitrite level in serum as well as that produced by MDM culture at enrolment in subgroup I regardless of category of ARI developed on follow up while in subgroup II there was significant elevation in these levels at enrolment, more among cases developing PT than those developing non-PT category of ARI. The subgroup I demonstrated increased production of superoxide at enrolment. The present study suggested that depressed production of nitrite and IL-12p70 by macrophages induced by iron overload may be responsible for greater susceptibility of HIV-1 positive donors to M. tuberculosis while superoxide may be a less powerful anti-mycobacterial tool.

Possible Involvement of Nuclear Factor Kappa B in Rapid Disease Progression in ART Naive HIV-1 Infected Remunerated Blood Donors with History of Oral Iron Intake

A retrospective analysis on the assessment of the level of p65 component of the transcription factor Nuclear Factor Kappa B (NF-kB p65) in the nuclear extract of lipopolysaccharide stimulated peripheral blood mon-onuclear cells (PBMCs) of remunerated blood donors with HIV-1 infection revealed NF-kB p65 to be significantly higher in the subgroup with history of oral iron intake compared to the HIV-1 infected subgroup without such history. The level of NF-kB p65 in iron consuming subgroup of HIV-1 positive donors showed positive correlation with the serum ferritin level and with the rate of increase in viral load. The NF-kB p65 level also showed positive correlation with the level of superoxide produced by cultured Monocyte derived macrophages (MDMs) as well as with the levels of the immune activation markers viz. Tumour necrosis factor alpha (TNF-α) and two of its soluble markers i.e. Tumour necrosis factor receptor types one and two (TNFRI and TNFRII) reported in earlier studies in the same subgroup. The opposing roles of NF-kB in situation of iron overload in HIV-1 infection i.e. disease enhancement on one hand and facilitation of effective antiretroviral therapy through activation of HIV-1 in the latently infected cells on other hand suggest the need for further research to weigh benefits and risks of iron therapy in situations where iron deficiency in HIV-1 infection may be a serious consideration.

Trace Element Levels, Cytokine Profile and Immune Activation Status in Plasma among Repeat Blood Donors with Asymptomatic HIV-1, HBV and HCV Infection

Imbalance of essential trace elements viz. Zinc, Selenium, Iron, Copper and Magnesium has been reported to influence disease course in HIV-1, HBV and HCV infections by altering immune status. A study was taken up to examine plasma levels of Th1 (IFN-γ and IL-2) and Th2 (IL-4 and IL-10) categories of cytokines and immune activation markers (TNF-α, TNFR I and TNFR II) in an asymptomatic group of HIV-1, HBV and HCV infected blood donors in relation to trace elements. Plasma levels of Zn, Se and Mg were depressed in all the three groups of blood donors (P < 0.001 for all). Levels of Cu and Fe were depressed in HIV-1 infection (P < 0.001 for both), but elevated in HBV and HCV infections (P < 0.015 and < 0.001 for Cu and < 0.001 for Fe in case of HBV and HCV infections respectively). IL-2 and IFN-γ were depressed in all the three groups of blood donors (P < 0.001). IL-4 and IL-10 levels were elevated in HBV and HCV infections (P < 0.001 for both). Immune activation markers were elevated in all the three groups of blood donors (P < 0.001 for all). HIV-1 infection showed positive correlations between Cu and IL-2, Zn and IFN-γ, and in HBV infection while positive correlations were found between Mg and TNFR I and TNFR II and Se with TNFR II. HCV infection showed a positive correlation between Se and IFN-γ (P < 0.001), Mg and IL-4 (P = 0.02), Fe and IL-10 (P < 0.01). The present study reveals possible relationship between trace element level alterations and alterations in cytokine and immune activation levels in HIV-1, HBV and HCV infection.