Reply to comment on: Co-infection with subclinical HIV and Wuchereria bancrofti, and the role of malaria and hookworms, in adult Tanzanians: infection intensities, CD4/CD8 counts and cytokine responses

Abstract

We appreciate Dr Eisenhut's interest in our paper (Nielsen et al., 2007), which evolved from a previous cross-sectional study (Nielsen et al., 2006) in which a negative association between hookworm and HIV infection was found. As we pointed out, this association may reflect a cause—effect relationship but may also be caused by confounding. If the relationship is causal, the direction cannot be determined owing to the cross-sectional nature of the study. In our recent study (Nielsen et al., 2007), we presented a higher CD4% and CD4/CD8 ratio in HIV-positive individuals with hookworm co-infection than in HIV-positives without hookworm infection, which may be due to a cause–effect relationship or a result of confounding effects. Among other suggestions, we introduced immunological hyporesponsiveness and thereby reduced replication of HIV virus induced by chronic hookworm infection (Borkow and Bentwich, 2004) as a possible underlying mechanism of a negative association between HIV and hookworm infection. Dr Eisenhut questions the plausibility of our explanation and made the point that hyporesponsiveness would lead to an on average smaller number of white cells, including CD4 lymphocytes, in response to infection. We acknowledge this point, but find that it does not exclude the possibility of reduced HIV virus replication (due to a hookworm-induced general immunological hyporesponsiveness) in the remaining CD4 cells and thereby a reduced rate of CD4 cell destruction in hookworm-infected individuals. This is to be compared with HIV-positive individuals without hookworms with a then relatively higher number of CD4 cells but, owing to the lack of hookworm-induced hyporesponsiveness, also a higher level of virus replication and CD4 cell destruction. Based on this hypothesis, it is difficult to predict which of the two groups would have the highest CD4 count, but at some point the negative effect of the hyporesponsiveness (decrease in CD4 cells) might be exceeded by a positive effect (reduced destruction of CD4 cells) in co-infected individuals, resulting in a higher number of CD4 cells in hookworm-infected HIV-positive individuals than in HIV-positives without hookworms. The level of CD4 count in the two groups at a given point would obviously depend on the stage of the HIV infection and perhaps also on the intensity of the hookworm infection. Thus, we concur with Dr Eisenhut's suggestion of including data on infection history in future studies aimed at elucidating HIV and helminth interactions. The possibility that the better immune status in hookworm-infected HIV-positive individuals reflects the fact that these individuals have been infected with HIV more recently is plausible and should have been discussed in our paper (Nielsen et al., 2007). It is well established that HIV infection impairs nutritional status and that low nutritional status may affect the course of HIV infection (Fawzi et al., 2004). We therefore support the suggestion of including indicators of malnutrition whenever possible in studies involving HIV-infected individuals.