Background
Despite the efficacy of contemporary antiretroviral therapy (ART) regimens, some people with HIV (PWH) experience persistent low-level viremia (pLLV). pLLV risk factors include poor ART adherence, high viral loads (VLs) pre-ART, and co-infection. Importantly, HIV and malaria, caused by Plasmodium infection, are geographically co-endemic and both pathogens persist in the gastrointestinal (GI) tract. However, how HIV/Plasmodium co-infection influences pLLV is unknown. Furthermore, the impact of pLLV on the GI tract, particularly in the context of co-infection, is poorly understood. Here, we used a rhesus macaque (RM) model of SIV/P. fragile co-infection to characterize clinical and immunological differences between ART-treated RMs that were incomplete virologic responders (IVRs) with pLLV and ART-responders, with the goal of identifying biologic determinants of pLLV in the setting of ART adherence and co-infection.
Methods
Male (n=6) RMs were intravenously (i.v.) inoculated with SIVmac239 (TCID50=50); initiated ART at Week(W) 8 post-SIV infection (p.i.); were i.v. inoculated with P. fragile (20×10^6 infected erythrocytes) at W12 p.i.; and euthanized at W20 p.i.. Plasma VL, anemia and peripheral parasitemia were monitored via qPCR, clinical blood counts, and Geimsa-staining, respectively. CD4+ T-cell absolute counts and GI immune cell frequencies were assessed using flow cytometry.
Results
All RMs exhibited clinical signs of malaria post-P. fragile co-infection. Prior to ART VLs were non-significantly higher (P=0.093) and significantly increased post P. fragile co-infection (P=0.034) in IVRs (n=3) as compared to ART-responders (n=3). Absolute CD4+ T-cell counts were similar between IVRs and ART-responders prior to ART, but were non-significantly higher (P=0.069) in IVRs as compared to ART-responders following P. fragile co-infection. In the duodenum, an SIV reservoir and site of P. fragile sequestration, neutrophil frequencies were significantly increased in ART-responders compared to IVRs following P. fragile co-infection (P= 0.046).
Conclusions
IVRs had elevated pre-ART and post-P. fragile VLs, higher CD4+ T cells post-P. fragile, and fewer GI neutrophils post-P. fragile as compared to ART-responders, suggesting an ineffective GI neutrophil response during P. fragile co-infection could influence the viral reservoir and contribute to pLLV during ART-treated SIV infection.
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