HIV and Malaria Co-Infection: A Game of Immunological Russian Roulette

Around the world, there are approximately 300 million cases of malaria, from which 1 million deaths occur (1). In 2010 alone, the number of people infected with HIV increased by 2.7 million, altogether amounting to 36.7 million HIV-infected individuals globally (2). Both “diseases of poverty”, malaria and HIV have similar geographical distributions, prevalent particularly in third-world sub-Saharan Africa, the Indian subcontinent, and Southeast Asia. Studies have shown that due to this geographical overlap, co-infection of the two diseases is a common phenomenon in these regions (3,4).

HIV/AIDS is brought about by a virus whereas malaria is caused by a plasmodium. Co-infection of the two diseases, therefore, has great potential towards the investigation of dynamics between the mechanisms of immune response to both infections. Ryan-Payseur, et al., in this paper, are looking to elucidate just that; that is, what exactly happens to the immune system when it is infected by a virus and a parasite? This is an interesting paper because in research, it is difficult to examine the effects of co-infection in naturally occurring infections because naïve individuals do not exist—humans co-infected with HIV and malaria often have been previously exposed to malaria, which can complicate results (5). Nevertheless, the researchers for this paper were able to circumvent this problem, as well as the additional problem of an accurate animal model (Fig. 1), through a series of imaginative tweaks to the primate model of Simian Immunodeficiency Virus (SIV)-plasmodium infection.

[ Fig. 1 ]

First, the researchers got a hold of 19 naïve Chinese rhesus macaques—4-8 years old; who had never been exposed to infection by the simian retrovirus, simian T-lymphotrophic virus type 1, and SIV. Just as SIV pathogenesis differs from HIV pathogenesis, there are pathological differences in P. falciparum infection between humans and macaques (6). The researchers developed the SHIV89.6P/P. fragile model that was unique to macaques (Fig. 2). To make sure these macaques would definitely transition to AIDS, they specifically used the SHIV strain, “SHIV89.6P”. The researchers then split up their naïve Chinese rhesus macaques, and infected them in 4 batches (Fig. 3).

[ Fig. 2 ]
[ Fig. 3 ]

2-3 weeks after infection, the researchers collected blood and tissue samples from each batch. The two co-infection batches turned out contrasting results. Surprisingly, the “chronic SHIV/malaria” batch was safe, whereas the “acute SHIV/malaria” batch was severely affected by the co-infection, demonstrated by a faster progression to AIDS and death from fatal malaria. The “acute SHIV/malaria” macaques had MUCH higher levels of parasitemia (plasmodium-infection) than “chronic SHIV/malaria” macaques. Both batches were treated with chloroquine, an anti-malarial drug, to clear the infection; despite having taken the drug, the acutely infected macaques still became moribund. Interestingly though, the chronically infected macaques all survived after chloroquine treatment.

Also of interest was the number of blood CD4+ and CD8+ T cells present in each infection batch. CD4+ T cells (a.k.a. “helper T cells”) are a kind of white blood cell (lymphocyte) that play a huge part in the immune system. They generally don’t have any cell/pathogen-killing (cytotoxic) or pathogen–eating (phagocytic) abilities themselves, but are extremely important in activating and directing other immune cells (B cells, cytotoxic T cells, and macrophages, for example). Basically, these CD4+ cells are to the rest of the immune system what Alfred is to Batman; M is to James Bond; Basil Exposition is to Austin Powers (…you get my drift).

More significantly, CD4+ T cells are the preferred sites of replication for S/HIV because of the CD4 co-receptor that is expressed on these cells. Viral replication depletes the CD4+ T cell count, which eventually makes the infected individual immunodeficient, causing acquired immunodeficiency syndrome (AIDS). The CD4+ T cell count in a S/HIV-infected individual indicates the severity of the infection and how close the individual is to developing AIDS (10). To track the functions of the CD4+ T cells, the researchers stained for the presence of the pathogen-combating cytokines, IFN-g, TNF-a, IL-17, and IL-22, using immunofluorescence and flow cytometry.

The chronic batch had low magnitude increases in SHIV viremia and a stable CD4+ T cell count. The progression to AIDS in this batch of macaques was therefore slow. The acute batch, on the other hand, had extreme downregulation of CD4+ T cells, which means that SHIV was replicating at high rates. Histological staining showed high levels of necrosis of lymphoid tissues in the lymph nodes, spleen and gut mucosae in the acute batch. Such tissue necrosis is rarely seen even in the advanced stages of AIDS, so malaria had to be the culprit (7). Also, by comparing with the induction levels in the “malaria-only” batch, it looked as though malaria was causing the expansion CD4+ and CD8+ T effector cells (which secrete IFN-g and TNF-a) to go into overdrive in the acute batch.

"Well, Austin…" this means that in “acute SHIV/malaria” co-infection, SHIV and malaria exist in a mutually dependent manner (Fig. 4) to wreak the most havoc on the infected individual (like "sharks with frickin' laser beams attached to their heads", perhaps?). Fatality signs include widespread lymphoid necrosis through the lymph nodes, spleen and gut mucosae, hyperactivation of CD4+ and CD8+ T effector cells to secrete cytokines, HIV-induced downregulation of CD4+, and the upregulation of parasitemia. All these signs lead to fatal malaria, and a rapid progression to AIDS.

[ Fig. 4 ]

Having seen what happens during acute SHIV/malaria co-infection, the question arises, then, of how in the world the “chronic SHIV/malaria” batch managed to survive co-infection? The researchers saw that chronically infected macaques suppressed Th1 effector expression after malarial co-infection, but upregulated IL-17 and IL-22-secreting CD4+ T cells (Th17 and Th22, respectively) by up to 200 fold. IL-22 is generally suppressed by the presence of Th1, so this upregulation is expected. IL-17 and IL-22 are generally antimicrobial cytokines that play a role in the recruitment and activation of neutrophils (9). Therefore, without Th1 effector cells to induce widespread necrosis and HIV replication that would foster malarial infection, it is likely that IL-17 and IL-22 were working in tandem to provide full immuno-protection against malaria. This explains why the "chronic SHIV/malaria" batch of macaques showed low levels of both viremia and parasitemia compared to the acute batch, in addition to a low and stable CD4+ T cell count throughout the experimental period.

This paper is the first to show that the Th1 or Th17/IL-22 response is preferentially triggered upon acute or chronic co-infection of SHIV with malaria. The manipulation of this dichotomous response has much potential in the development of AIDS, as well as malaria vaccines. However, before we can think about vaccines, we must answer this question: what exactly about chronic infection suppresses the Th1 effector response and favors the Th17 response instead?

It has been shown that Th17 cells are NOT preferentially infected in peripheral blood (8), which is where the blood samples for this paper were derived. This could explain the upregulation of Th17 cells in the chronically infected macaques--it could be that Th1 cells were not being suppressed but were being depleted due to the HIV infection. However, it is not confirmed that this protection from infection only occurs in chronically infected individuals. For that reason, the mechanisms to this preferential response are still to be investigated. Until then, HIV/malaria co-infection is like a game of Russian roulette: depending on the luck of an HIV-infected individual (and at what stage of HIV infection he is), a co-infection with the relatively milder disease has the potential to either keep him safe or, quite the opposite, kill him.

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Primary Reference:

1) Ryan-Payseur, B., et al. 2011. Virus Infection Stages and Distinct Th1 or Th17/Th22 T-Cell Responses in Malaria/SHIV Coinfection Correlate with Different Outcomes of Disease. J Infect Dis. 204:1450-62.

Secondary References:

1) http://www.who.int/topics/malaria/en/index.html

2) http://www.who.int/hiv/data/2011_epi_core_en.png

3) Hochman, S., Kim, K. 2009. The Impact of HIV and Malaria Coinfection: What Is Known and Suggested Venues for Further Study. Interdisciplinary Perspectives on Infectious Diseases. 2009(617954):1-8.

4) Slutsker, L., Marston, B.J. 2007. HIV and malaria: Interactions and Implications. Curr Opin Infect Dis. 20:3-10.

5) Troye-Blomberg, M., Berzins, K. 2008. Immune interactions in malaria co-infections with other endemic infectious diseases: implications for the development of improved disease interventions. Microbes Infect. 10:948-52.

6) Collins, W.E., Warren M., Sullivan J.S., et al. 2006. Studies on sporozoite-induced and chronic infections with Plasmodium fragile in Macaca mulatta and New World monkeys. J Parasitol. 92:1019-26.

7) Hemmer, C.J., et al. 1992. Soluble tumor necrosis factor receptors correlate with parasitemia and disease severity in human malaria. J Infect Dis. 166(4): 930-934.

8) Brenchley, J. M., et al. 2008. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 112:2826–2835.

9) O’ Connor Jr, W., et al. 2010. The dual nature of T(H)17 cells: shifting the focus to function. Nat Immunol. 11:471-6.

10) Meyaard, L., et al. 1992. Programmed death of T cells in HIV-1 infection. Science. 257(5067):217-219.