Walk on the wild side: SIV infection in African non-human primate hosts—from the field to the laboratory

Abstract

HIV emerged following cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect non-human primates (NHPs) from Africa. While HIV replication and CD4+ T-cell depletion lead to increased gut permeability, microbial translocation, chronic immune activation, and systemic inflammation, the natural hosts of SIVs generally avoid these deleterious consequences when infected with their species-specific SIVs and do not progress to AIDS despite persistent lifelong high viremia due to long-term coevolution with their SIV pathogens. The benign course of natural SIV infection in the natural hosts is in stark contrast to the experimental SIV infection of Asian macaques, which progresses to simian AIDS. The mechanisms of non-pathogenic SIV infections are studied mainly in African green monkeys, sooty mangabeys, and mandrills, while progressing SIV infection is experimentally modeled in macaques: rhesus macaques, pigtailed macaques, and cynomolgus macaques. Here, we focus on the distinctive features of SIV infection in natural hosts, particularly (1): the superior healing properties of the intestinal mucosa, which enable them to maintain the integrity of the gut barrier and prevent microbial translocation, thus avoiding excessive/pathologic immune activation and inflammation usually perpetrated by the leaking of the microbial products into the circulation; (2) the gut microbiome, the disruption of which is an important factor in some inflammatory diseases, yet not completely understood in the course of lentiviral infection; (3) cell population shifts resulting in target cell restriction (downregulation of CD4 or CCR5 surface molecules that bind to SIV), control of viral replication in the lymph nodes (expansion of natural killer cells), and anti-inflammatory effects in the gut (NKG2a/c+ CD8+ T cells); and (4) the genes and biological pathways that can shape genetic adaptations to viral pathogens and are associated with the non-pathogenic outcome of the natural SIV infection. Deciphering the protective mechanisms against SIV disease progression to immunodeficiency, which have been established through long-term coevolution between the natural hosts and their species-specific SIVs, may prompt the development of novel therapeutic interventions, such as drugs that can control gut inflammation, enhance gut healing capacities, or modulate the gut microbiome. These developments can go beyond HIV infection and open up large avenues for correcting gut damage, which is common in many diseases.

Adaptation of SIVmac to baboon primary cells results in complete absence of in vivo baboon infectivity

“…Eleven candidate non-synonymous nucleotide variations that increased in frequency during PBMC passage mapped to Env; three of these fell within or very close to the V3 loop. Changes in co-receptor tropism or affinity are typically attributed to sequence variations within this region (Hwang et al, 1991;Ivanoff et al, 1992;Trujillo et al, 1996). We previously identified one mechanism of SIVmac restriction in baboon PBMC that involves increased production of CCR5 ligands (CCL3, CCL4, and CCL5) that interfere with viral entry (Obregon-Perko et al, 2018).…”

Adaptation of SIVmac to baboon primary cells results in complete absence of in vivo baboon infectivity

“…Eleven candidate non-synonymous nucleotide variations that increased in frequency during PBMC passage mapped to Env; three of these fell within or very close to the V3 loop. Changes in co-receptor tropism or affinity are typically attributed to sequence variations within this region (Hwang et al, 1991;Ivanoff et al, 1992;Trujillo et al, 1996). We previously identified one mechanism of SIVmac restriction in baboon PBMC that involves increased production of CCR5 ligands (CCL3, CCL4, and CCL5) that interfere with viral entry (Obregon-Perko et al, 2018).…”

A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection

“…SIVs are believed to be generally non-pathogenic in their reservoir hosts with the SIVsmm in sooty mangabeys and SIVagm in African green monkeys as the best studied examples ( Jasinska et al, 2023 ). SIVcpz in naturally infected chimpanzees is pathogenic although not to the extent of HIV-1 group M infection of untreated humans ( Keele et al, 2009 ).…”

Finetuning Type I Interferon Signaling to Enhance T Cell Immunity in HIV Infection

“…Natural hosts of Simian immunodeficiency virus (SIV), such as African green monkeys and sooty mangabeys, exhibit a controlled immune response where ISG expression spikes during acute infection but is quickly downregulated in the chronic phase, allowing them to avoid long-term immune activation [ 66 , 67 , 68 ]. In contrast, non-natural hosts like macaques experience prolonged ISG activation, which drives chronic inflammation and progression to AIDS [ 69 , 70 , 71 , 72 ]. These early findings demonstrated how an unregulated type I IFN response can transform an initially protective antiviral mechanism into a driver of immune dysfunction.…”

Adaptation of SIVmac to baboon primary cells results in complete absence of in vivo baboon infectivity

“…Eleven candidate non-synonymous nucleotide variations that increased in frequency during PBMC passage mapped to Env; three of these fell within or very close to the V3 loop. Changes in co-receptor tropism or affinity are typically attributed to sequence variations within this region (Hwang et al, 1991;Ivanoff et al, 1992;Trujillo et al, 1996). We previously identified one mechanism of SIVmac restriction in baboon PBMC that involves increased production of CCR5 ligands (CCL3, CCL4, and CCL5) that interfere with viral entry (Obregon-Perko et al, 2018).…”

A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection

“…SIVs are believed to be generally non-pathogenic in their reservoir hosts with the SIVsmm in sooty mangabeys and SIVagm in African green monkeys as the best studied examples ( Jasinska et al, 2023 ). SIVcpz in naturally infected chimpanzees is pathogenic although not to the extent of HIV-1 group M infection of untreated humans ( Keele et al, 2009 ).…”

Finetuning Type I Interferon Signaling to Enhance T Cell Immunity in HIV Infection

“…Natural hosts of Simian immunodeficiency virus (SIV), such as African green monkeys and sooty mangabeys, exhibit a controlled immune response where ISG expression spikes during acute infection but is quickly downregulated in the chronic phase, allowing them to avoid long-term immune activation [ 66 , 67 , 68 ]. In contrast, non-natural hosts like macaques experience prolonged ISG activation, which drives chronic inflammation and progression to AIDS [ 69 , 70 , 71 , 72 ]. These early findings demonstrated how an unregulated type I IFN response can transform an initially protective antiviral mechanism into a driver of immune dysfunction.…”

Adaptation of SIVmac to baboon primary cells results in complete absence of in vivo baboon infectivity

“…Eleven candidate non-synonymous nucleotide variations that increased in frequency during PBMC passage mapped to Env; three of these fell within or very close to the V3 loop. Changes in co-receptor tropism or affinity are typically attributed to sequence variations within this region (Hwang et al, 1991;Ivanoff et al, 1992;Trujillo et al, 1996). We previously identified one mechanism of SIVmac restriction in baboon PBMC that involves increased production of CCR5 ligands (CCL3, CCL4, and CCL5) that interfere with viral entry (Obregon-Perko et al, 2018).…”

A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection

“…SIVs are believed to be generally non-pathogenic in their reservoir hosts with the SIVsmm in sooty mangabeys and SIVagm in African green monkeys as the best studied examples ( Jasinska et al, 2023 ). SIVcpz in naturally infected chimpanzees is pathogenic although not to the extent of HIV-1 group M infection of untreated humans ( Keele et al, 2009 ).…”

Finetuning Type I Interferon Signaling to Enhance T Cell Immunity in HIV Infection

“…Natural hosts of Simian immunodeficiency virus (SIV), such as African green monkeys and sooty mangabeys, exhibit a controlled immune response where ISG expression spikes during acute infection but is quickly downregulated in the chronic phase, allowing them to avoid long-term immune activation [ 66 , 67 , 68 ]. In contrast, non-natural hosts like macaques experience prolonged ISG activation, which drives chronic inflammation and progression to AIDS [ 69 , 70 , 71 , 72 ]. These early findings demonstrated how an unregulated type I IFN response can transform an initially protective antiviral mechanism into a driver of immune dysfunction.…”