Evidence for an Increased Risk of Transmission of Simian Immunodeficiency Virus and Malaria in a Rhesus Macaque Coinfection Model

Abstract

In sub-Saharan Africa, HIV-1 infection frequently occurs in the context of other coinfecting pathogens, most importantly, Mycobacterium tuberculosis and malaria parasites. The consequences are often devastating, resulting in enhanced morbidity and mortality. Due to the large number of confounding factors influencing pathogenesis in coinfected people, we sought to develop a nonhuman primate model of simian immunodeficiency virus (SIV)-malaria coinfection. In sub-Saharan Africa, Plasmodium falciparum is the most common malaria parasite and is responsible for most malaria-induced deaths. The simian malaria parasite Plasmodium fragile can induce clinical symptoms, including cerebral malaria in rhesus macaques, that resemble those of P. falciparum infection in humans. Thus, based on the well-characterized rhesus macaque model of SIV infection, this study reports the development of a novel rhesus macaque SIV-P. fragile coinfection model to study human HIV-P. falciparum coinfection. Using this model, we show that coinfection is associated with an increased, although transient, risk of both HIV and malaria transmission. Specifically, SIV-P. fragile coinfected macaques experienced an increase in SIV viremia that was temporarily associated with an increase in potential SIV target cells and systemic immune activation during acute parasitemia. Conversely, primary parasitemia in SIV-P. fragile coinfected animals resulted in higher gametocytemia that subsequently translated into higher oocyst development in mosquitoes. To our knowledge, this is the first animal model able to recapitulate the increased transmission risk of both HIV and malaria in coinfected humans. Therefore, this model could serve as an essential tool to elucidate distinct immunological, virological, and/or parasitological parameters underlying disease exacerbation in HIV-malaria coinfected people.

Immune Activation and Regulation in Simian Immunodeficiency Virus-Plasmodium fragile-Coinfected Rhesus Macaques

“…Tissues, plasma, and cell suspensions were collected from adult male rhesus macaques infected with SIV or Plasmodium fragile or coinfected with both, as previously described (9). Animals were obtained from the California National Primate Research Center (CNPRC) and housed in accordance with the regulations of the American Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) at the CNPRC.…”

“…Coinfected animals were inoculated with SIV 28 days prior to P. fragile infection. Groups consisted of the following animals: SIV (32975 and 33677), P. fragile (33308, 33959, and 36346), and SIV-P. fragile (35914, 37007, and 37009) (9).…”

“…Reasoning that primary parasitemia represents a very early time point in coinfection, we hypothesized that altered innate responses must have contributed to the temporarily reduced control of virus and parasite replication. The current study used archived specimens from the animals of our previously described study (9) and focused on the functional analysis of myeloid dendritic cells and monocytes/macrophages as key players in pathogen recognition, antigen presentation, and induction of adaptive immune responses, as well as in the balance between immune activation and regulation.…”

“…If we can define specific immune mechanisms that are altered in coinfection compared to infection with either pathogen alone, we might be able to develop more effective intervention methods. Toward this goal, we developed a rhesus macaque model of simian immunodeficiency virus (SIV)-Plasmodium fragile coinfection to study HIV-P. falciparum infection in humans (9). Using this model, we were able to demonstrate that SIV-P. fragile-coinfected rhesus macaques experienced increased viremia and gametocytemia during primary parasitemia (9), a finding consistent with human data showing the potential for an increased transmission risk of both HIV and malaria in coinfected individuals (3-5, 10, 11).…”

“…Toward this goal, we developed a rhesus macaque model of simian immunodeficiency virus (SIV)-Plasmodium fragile coinfection to study HIV-P. falciparum infection in humans (9). Using this model, we were able to demonstrate that SIV-P. fragile-coinfected rhesus macaques experienced increased viremia and gametocytemia during primary parasitemia (9), a finding consistent with human data showing the potential for an increased transmission risk of both HIV and malaria in coinfected individuals (3-5, 10, 11). Reasoning that primary parasitemia represents a very early time point in coinfection, we hypothesized that altered innate responses must have contributed to the temporarily reduced control of virus and parasite replication.…”