Background:
We aim to understand the degree and duration of protection induced by HIV treatment killing of malaria parasites (called infection-treatment vaccination or ITV, alternatively referred to as chemoprophylaxis vaccination or CVac), and the role of such ITV in acquired, malaria specific anti-infection immunity in the field. We also aim to study the effects of HIV treatments on malaria transmission. Naturally acquired immunity to malaria only develops after a number of disease episodes, and is imperfect as it fails to protect against infection. Blood stage (BS) malaria infection, which is the stage associated with malaria clinical symptoms, may prevent anti-infection immune responses. In contrast, complete protective anti-infection immunity is induced with attenuated malaria parasites that arrest during liver stage development. Anti-infection immunity is also observed in mice that are infected with wildtype sporozoites (the infective form of the parasite) and then given drugs that kill LS parasites, and in humans that are infected with wildtype parasites while receiving chloroquine, a drug that kills BS parasites. Also, chemoprophylaxis studies in endemic areas likely failed to induce anti-infection immunity as the drug regimens employed may have permitted BS exposure. Taken together, these data indicate that exposure to LS parasites and avoidance of BS infection can induce highly effective anti-infection immunity. Pre-clinical data show that HIV protease inhibitors (HIV PIs), but not non-nucleoside reverse transcriptase inhibitors (NNRTIs) have anti-BS activity, but effects on LS parasites require further study. Separately, the antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) reduces clinical malaria episodes presumably from an anti-BS effect, but whether an anti-LS effect occurs and how this may contribute to anti-infection immunity is unknown. ITV-like effects might occur in naturally exposed populations who are receiving HIV treatments with antimalarial effects. Also, because these drugs are taken continuously, they may be more likely to attenuate LS and prevent BS infection via constant pressure, although the degree of effect will likely depend on transmission intensity and host immunologic status. Separately, HIV PIs have been shown to affect sexual stage parasites (gametocytes), but their effects on later stage gametocytes and mosquito stage parasites (TS) remains unknown. Also, while other antifolates may not kill gametocytes but do kill mosquito stages, effect of TMP-SMX on TS requires further investigation. We hypothesize that 1) HIV PIs and TMP-SMX will kill LS and TS parasites at clinically relevant concentrations (CRCs), that is, concentrations achieved in the serum of patients on standard dosing regimens; 2) the use of drugs with LS-killing effects will contribute to acquisition of anti-infection immunity in areas where African children who receive these treatments; and 3) HIV treatments with TS-killing effects will contribute to reduced transmission. Based on these hypothesis, we propose the following projects and summarize our accomplishments: PROJECT 1: To examine the impact of HIV treatments on malaria liver stages (LS) and anti-infection immunity in vitro and in animal models at clinically relevant concentrations (CRCs). Significance: Because each of these HIV treatments are used in malaria-endemic areas, we believe our in vitro and animal data will provide evidence for further investigation of HIV treatment effects in the field. HIV treatment regimens (choice, and in the case of TMP-SMX prophylaxis, duration) could be tailored for patients in malaria-endemic areas if these drugs reduce malaria burden. Major Findings/Progress: 1) The HIV PI lopinavir, and the antimicrobial TMP-SMX, but not the NNRTI nevirapine, kills P. falciparum LS in vitro at clinically relevant concentrations (CRCs) and 2) Repeated exposures to live sporozoites with TMP-SMX prophylaxis induces development anti-infection, sustained, stage-specific immunity PROJECT 2: To examine the impact of HIV treatments on malaria gametocytes, mosquito stages, and transmission in vitro. Significance: HIV-infected patients population (especially those with more severe immunocompromise) have higher parasite burdens and more frequent malaria. HIV treatments that reduce transmission may contribute to reduced malaria burden at a community level. Major Findings/Progress: The HIV PI lopinavir, but not the NNRTI, nevirapine, kills gametocytes (A) and mosquito stages (B) of P. falciparum in vitro at clinically relevant concentrations (CRCs). TMP-SMX does not kill gametocytes, but kills mosquito stages at CRCs. PROJECT 3: To examine the impact of HIV treatments on malaria infection incidence and anti-infection immunity in HIV-infected or HIV-exposed, uninfected African children. Significance: Currently, the World Health Organization recommends HIV management with antiretroviral therapy (ART): first line regimens include an NNRTI (in children, nevirapine) and 2 nucleoside reverse transcriptase inhibitors (NRTIs) with few exceptions, and second line regimens include an HIV PI (in children, lopinavir-ritonavir) and 2 NRTIs. Separately, TMP-SMX is used in HIV-exposed, uninfected children in resource-limited settings for extended durations because children in such settings breastfeed out of necessity, which poses a continued risk for HIV transmission. Extending or curtailing the duration of TMP-SMX prophylaxis has been a source of debate due to concerns over development of antibacterial TMP-SMX resistance. If any drugs used in HIV management are deemed to have an effect in reducing the clinical burden of malaria, either by direct drug-parasite killing effect on LS or TS, or via an ITV-like induction of immunity, their use may become tailored to maximize parasite killing and protective anti-infection immunity, and to minimize transmission. Major Findings/Progress: Our observational substudy examining HIV PIs vs. NNRTIs (in collaboration with the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, or IMPAACT) has reached full enrollment at 3 sites, and these children have now been followed for over 2 years. Samples processing as well as data analysis is ongoing. Separately, our study examining TMP-SMX effect on malaria infection and anti-infection immunity is in planning stages. PROJECT 4: To examine the impact of HIV treatments on malaria transmission in HIV-infected or HIV exposed, uninfected African children. Significance: HIV treatments may impact malaria parasite transmission in the community. If certain HIV treatments contribute to reduction of transmission, their use may become standardized (i.e., HIV PIs preferentially used in malaria endemic areas) or timed to capitalize on such effects (i.e., TMP-SMX prophylaxis in HIV-uninfected children extended). Major Findings/Progress: Our observational substudy (examining HIV PIs vs. NNRTIs) has reached full enrollment and these children have now been followed for over 2 years. Samples collection and processing as well as data analysis is ongoing. Our study examining TMP-SMX effect on malaria infection and anti-infection immunity is in planning stages.
