HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co- infecting pathogens. However, many aspects of this interaction have not been fully delineated. We hypothesize that dual infection causes increased HIV expression and more rapid HIV disease progression and that activation of malaria-specific CD4+ T-cells in the presence of uncontrolled HIV replication leads to depletion of malaria -specific immunity. To better understand the effects of P. falciparum on HIV, we studied the interaction ex vivo using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial and we used an in vitro co-culture system to study the mechanisms contributing to increased viral replication. To assess the effects of HIV on P. falciparum, we took advantage of a recently completed clinical trial of antiretroviral therapy to study the relationship between subpatent parasitemia (detection of parasites by methods more sensitive than blood smears, but without clinical malaria) and clinical disease and attempted to assess whether the HIV-1 protease inhibitor (PI) atazanavir reduced the rate of detection of plasma P. falciparum DNA. The ex vivo experiments showed an increase in HIV production and pro- inflammatory cytokine secretion that occurred after the parasitemia and generalized immune activation resolved, suggesting that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines. We also demonstrated that phagocytic, antigen presenting cells ingest P. falciparum infected red blood cells and stimulate CD4+ T-cells to produce HIV-1 in a cytokine- and contact-dependent manner. Lastly, subpatent parasitemia was not significantly associated with clinical malaria and HIV PI therapy did not decrease the prevalence of parasitemia. Taken together, our results suggest that while subpatent parasitemia may not lead to clinical disease, it may contribute to an increase in plasma HIV-1 RNA levels in untreated patients, especially upon repeat encounters with malaria parasites. It is plausible that any level of parasitemia may contribute to CD4+ T-cell activation, even in the presence of anti-retroviral therapy. Thus, it may be important to suppress parasitemia in HIV seropositive individuals, even if they are asymptomatic

Background

Plasmodium falciparum infection induces human immunodeficiency virus (HIV) replication and accelerates a decline in CD4(+) T-cell count. The mechanisms contributing to these interactions have not been fully elucidated.

Methods

We infected peripheral blood mononuclear cells (PBMCs) with HIV type 1 (HIV-1) and then cocultured them with P. falciparum-infected red blood cells (iRBCs) or uninfected RBCs (uRBCs). Levels of HIV-1 p24 antigen and activation-associated cytokines were measured in culture supernatants. T-cell surface activation was assessed by flow cytometry.

Results

It has been reported that iRBCs increase HIV replication, compared with uRBCs; that neutralizing tumor necrosis factor α (TNF-α) abrogates this increase; and that hemozoin enhances HIV production. In this study, we confirmed that TNF-α plays an important role in this interaction. We show that iRBCs increased CD4(+) T-cell expression of HLA-DR(+)/CD38(+) (P = .001), that monocyte/macrophage depletion reduced HIV production by 40%-50% (P < .001), and that hemozoin-laden monocytes/macrophages that were preincubated with iRBCs also stimulated HIV production.

Conclusions

iRBCs activate CD4(+) T cells and stimulate HIV replication in a TNF-α-dependent manner following malarial antigen processing by monocytes/macrophages. These results suggest that the persistent elevation of HIV replication during and after acute bouts of P. falciparum malaria may be due, at least in part, to ongoing stimulation of CD4(+) T cells by hemozoin-loaded antigen-presenting cells within lymphoid tissues.

Background

HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co-infecting pathogens. We examined the relationship between presence of P. falciparum DNA in plasma samples and clinical malaria as well as the impact of atazanavir, an HIV-1 protease inhibitor (PI), on P. falciparum PCR positivity.

Methods

ACTG study A5175 compared two NNRTI-based regimens and one PI-based anti-retroviral (ARV) regimen in antiretroviral therapy naïve participants. We performed nested PCR on plasma samples for the P. falciparum 18s rRNA gene to detect the presence of malaria DNA in 215 of the 221 participants enrolled in Blantyre and Lilongwe, Malawi. We also studied the closest sample preceding the first malaria diagnosis from 102 persons with clinical malaria and randomly selected follow up samples from 88 persons without clinical malaria.

Results

PCR positivity was observed in 18 (8%) baseline samples and was not significantly associated with age, sex, screening CD4+ T-cell count, baseline HIV-1 RNA level or co-trimoxazole use within the first 8 weeks. Neither baseline PCR positivity (p = 0.45) nor PCR positivity after initiation of antiretroviral therapy (p = 1.0) were significantly associated with subsequent clinical malaria. Randomization to the PI versus NNRTI ARV regimens was not significantly associated with either PCR positivity (p = 0.5) or clinical malaria (p = 0.609). Clinical malaria was associated with a history of tuberculosis (p = 0.006) and a lower BMI (p = 0.004).

Conclusion

P. falciparum DNA was detected in 8% of participants at baseline, but was not significantly associated with subsequent development of clinical malaria. HIV PI therapy did not decrease the prevalence of PCR positivity or incidence of clinical disease.

Abstract Background Plasmodium falciparum and HIV-1 infection cause substantial morbidity and mortality in sub-Saharan Africa. Increasing evidence suggests these two pathogens interact negatively when infecting the same individual. Methods A cross-sectional study among HIV-1 infected and uninfected populations was recruited in Mocuba and Maputo, Mozambique to determine the prevalence of sub-clinical malarial parasitaemia using light microscopy and a nested PCR assay. Results The prevalence of sub-clinical P. falciparum parasitaemia was low in Maputo, whether determined by microscopy (0.4%) or PCR (1.9%), but substantially higher in Mocuba (7.6 and 14.7%, respectively). Nested PCR detected nearly 70% more cases of sub-clinical parasitaemia than microscopy, but differences occur by locality. HIV-1 infected persons were more likely to be sub-clinically parasitaemic than HIV-1 uninfected individuals recruited from the same geographic areas. Trimethoprim-sulphamethoxazole use did not substantially reduce sub-clinical parasitaemia. Conclusions Dried blood spots are a convenient and sensitive technique for detecting sub-clinical infection with P. falciparum by nested PCR. Prevalence of P. falciparum is substantially lower in Maputo where malaria control programmes have been more active than in the rural town of Mocuba. In Mocuba, among those presenting for HIV-1 counseling and testing, the prevalence of P. falciparum is substantially higher in those who test positive for HIV-1 than those without HIV-1 infection. The clinical implications of sub-clinical P. falciparum infection among HIV-1 infected persons warrant additional study.