The proof-of-concept studies in macaque models of malaria/SHIV coinfection allowed us to make the novel observations that AIDS-virus infection stages dictate coinfection-induced immune responses and that distinct Th1 or Th17/IL-22+ immune responses correlate with different outcomes of SHIV disease and virus-associated malaria. Our studies extend human HIV/malaria coinfection studies [4
] and provide new information regarding pathogenesis of AIDS-virus and malaria coinfection. Our findings also suggest that macaque models of SHIV and P. fragile
can be useful for studying pathologic and immunologic events in human patients coinfected with HIV and P. falciparum
The macaque model of P. fragile
/acute SHIV coinfection suggests that malaria coinfection during acute AIDS-virus infection can induce fatal virus-associated malaria, characterized by bursting parasitemia and severe anemia. We temporarily use the term “fatal virus-associated malaria” because SHIV89.6P infection usually does not induce acutely fatal disease within a month after infection. Moreover, earlier reports and this study demonstrated that P. fragile
infection of naive macaques often does not induce acutely fatal malaria, although some individuals may develop complications due to unusually high-level parasitemia and associated anemia [13
]. The extraordinary effects of acute HIV or SIVmac infection on malaria coinfection in naive individuals have not been reported in humans or nonhuman primates, perhaps because of difficulty to recruit and study newly coinfected patients or because of previous exposures to malaria in the acutely AIDS virus–infected individual [4
Fatal virus-associated malaria and rapidly accelerated AIDS go hand-in-hand during P. fragile
/acute SHIV coinfection. CD4+ T-cell depletion appeared more profound in acute coinfected macaques than in SHIV-only controls. More importantly, dramatic lymphoid destruction/depletion and necrosis in lymph nodes and spleens were seen in malaria/acute SHIV coinfected monkeys as early as 21 days postinfection. Significant lymphoid depletion was also seen in gut mucosae. The rapid and profound lymphoid destruction/depletion and necrosis (temporarily defined as AIDS in the study) are attributed to malaria coinfection of acutely SHIV-infected macaques, because such fulminating changes can rarely be seen even in very advanced or end stages of AIDS induced by HIV, SIVmac, or SHIV. Such lymphoid destruction/necrosis might potentially occur in acute malaria/HIV coinfection, as P. fragile
causes P. falciparum–
like malaria [13
], and as SHIV induces simian AIDS–like HIV [15
The hyperactivation or expansion of IFNγ– and TNFα–producing CD4+ and CD8+ T effectors after malaria coinfection of acutely SHIV-infected macaques appears to be the mechanism underlying accelerated AIDS. This hyperactivation appeared to be driven mainly by malaria, because similar magnitudes of T effectors are detected in malaria-only controls, and SHIV-only control macaques did not develop detectable IFNγ–, IL-17–, or IL-22–producing CD4+ or CD8+ T effectors in either acute (3–4 week) or chronic SHIV infection ( and [15
]). Notably, because of SHIV coinfection, peak IFNγ plasma levels in malaria/acute SHIV–coinfected macaques were almost 100-fold higher than those in malaria-only controls. Hyperactivation of the immune system can readily transactivate the HIV 5′ LTR [33
] for massive viral replication, provide more CD4+ T cell or macrophage sources for productive virus infection, and make infected CD4+ T cells more susceptible to virus-mediated destruction [35
]. We did not detect much higher SHIV viral loads 2–3 weeks after acute SHIV/malaria coinfection than those on SHIV-only controls, perhaps because of extremely high turnover of virions in plasma during acute coinfection. The malaria/SHIV-driven hyperimmune activation may contribute to the profound lymphoid destruction/depletion and necrosis.
Because of acutely bursting SHIV replication, malaria-driven hyperactivation/expansion of Th1 effectors and overproduction of proinflammatory cytokines IFNγ and TNFα in malaria/acute SHIV-coinfected macaques might compromise antimalaria immune responses and lead to high-level parasitemia and fatal malaria. The extremely high-level Th1 cytokines in AIDS-virus coinfection may not be protective against malaria, as IFNγ has been shown to have a role in both protection and inflammation/pathology in malaria [24
]. Conversely, the suppression or disruption of CD4+ T cell-mediated antimalaria immunity may have taken place as a result of profound lymphoid destruction/depletion and necrosis. Because cell-mediated immunity is believed to occur primarily in the spleen for blood stage malaria [24
], profound lymphoid depletion in the spleen would lead to a loss of antimalaria effector function. Furthermore, the disappearance of germinal centers and lymphoid depletion of CD4+ T cells would block early development of antimalaria Ab responses.
One of the novel findings in the current study is that chronically SHIV-infected macaques employed a different defense mechanism to respond to malaria coinfection. In sharp contrast to acutely SHIV-infected macaques, chronically SHIV-infected macaques without AIDS showed marked suppression of Th1 responses after malaria coinfection. Rather, they mounted 50- to 200-fold expansion of IL-17–producing CD4+ T effectors, as well as unique, potent IL-22 responses. Unique expansion of IL-22–producing T effectors with Th1 suppression in malaria/chronic SHIV coinfection is consistent with our recent finding that IFNγ networking pathways can down-regulate IL-22+ T effector cells in tuberculosis [20
]. By mounting IL-17+ and IL-22+ T-cell responses and suppressing overreacting Th1 responses to malaria coinfection, chronically SHIV-infected macaques exhibit only transient, low-magnitude increases in viremia, maintain stable CD4+ T cell counts, and avoid rapid progression to AIDS. In addition, marked expansion of Th17 cells and unique increase in IL-22+ T effectors might act in concert with Ab and other immune components to attenuate moderately enhanced malaria in a timely manner, therefore avoiding fatal virus-associated malaria. IL-17 and IL-22 primarily act by recruitment of neutrophils and induction of antimicrobial peptide production by responder cells, and have been shown to have protective roles in infections of various pathogens, including toxoplasmosis [37
], candidiasis [38
], Klebsiella pneumonia
], and others (reviewed in [42
]). It would be interesting to see if these responses play a role in resistance to multiple malaria exposures in future studies.
Thus, our proof-of-concept study demonstrates for the first time to our knowledge that virus infection status and distinct Th1 or Th17/IL-22 responses after malaria coinfection of AIDS virus–infected individuals correlate with different clinical outcomes. As far as we know, this is also the first illustration of the dichotomy of Th1 and Th17/IL-22 responses during infection/coinfection of higher primates. The findings may be potentially useful in the development of AIDS and malaria vaccines and immunotherapeutics.