Mucosal Simian Immunodeficiency Virus Transmission in African Green Monkeys: Susceptibility to Infection Is Proportional to Target Cell Availability at Mucosal Sites

Pandrea, Ivona; Parrish, Nicholas F.; Raehtz, Kevin; Gaufin, Thaidra; Barbian, Hannah J.; Ma, Dongzhu; Kristoff, Jan; Gautam, Rajeev; Zhong, Fang; Haret-Richter, George S.; Trichel, Anita; Shaw, George M.; Hahn, Beatrice H.; Apetrei, Cristian

doi:10.1128/jvi.07141-11

Cited by 70 publications

(81 citation statements)

References 80 publications

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“…A recent report showed that AGMs are readily infected when mucosally inoculated with SIVagm at high viral titers, and that viral susceptibility correlated with higher levels of CCR5-expressing CD4 ϩ T cells in adult and juvenile AGMs, further supporting the notion that the paucity of CCR5-and CD4-expressing T cells in the infant gastrointestinal tract contributes to the rarity of vertical transmission in this species (55). While the limited availability of target cells likely contributes to the rarity of infant infection, SIV infection of the natural host species, sooty mangabeys, has been initiated in the setting of CCR5-null mutations (56).…”

Section: Discussionmentioning

confidence: 65%

Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

Amos

Wilks

Fouda

et al. 2013

J Virol

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Section: Discussionmentioning

confidence: 65%

Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

Amos

Wilks

Fouda

et al. 2013

J Virol

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“…ϩ T cells at the site of infection (28). Therefore, it is tempting to speculate that viral clearance results from the complete loss of CD4 ϩ T cells, and the data suggest that this loss in AGMs would not lead to immunodeficiency due to the immunological functioning of the CD8␣␣ T cells.…”

Section: Discussionmentioning

confidence: 99%

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Perkins

Briant

Calantone

et al. 2014

J Virol

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African green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIV AGM ). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4 T cells and a large population of major histocompatibility complex class II-restricted CD8␣ dim T cells that are generated through CD4 downregulation in CD4 ؉ T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here, we show that juvenile AGMs accelerate CD4-to-CD8␣␣ conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines interleukin-2 (IL-2), IL-7, and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans. IMPORTANCE Many African primate species are naturally infected with SIV. African green monkeys, one natural host species, avoid simian AIDS by creating a population of T cells that lack CD4, the human immunodeficiency virus/SIV receptor; therefore, they are resistant to infection. However, these T cells maintain properties of CD4؉ T cells even after receptor downregulation and preserve immune function. Here, we show that juvenile AGMs, who have not undergone extensive CD4 downregulation, accelerate this process upon SIV infection. Furthermore, we show that in vivo, CD4 downregulation does not occur exclusively in antigen-experienced T cells. Finally, we show that the cytokines IL-2, IL-7, and IL-15, which induce homeostatic T cell proliferation, lead to CD4 downregulation in vitro; therefore, they can provide signals that lead to antigen-independent CD4 downregulation. These results suggest that if a similar process of CD4 downregulation could be induced in humans, it could provide a cure for AIDS.

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“…Plasma SIVsabBH66 viral RNA loads were quantified by real-time PCR, as described previously (30,31). Whole blood and mononuclear cells isolated from intestinal biopsies were analyzed by flow cytometry, as described previously (9).…”

Section: Methodsmentioning

confidence: 99%

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

Kristoff¹,

Haret-Richter²,

Ma³

et al. 2014

J. Clin. Invest.

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Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.

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Mucosal Simian Immunodeficiency Virus Transmission in African Green Monkeys: Susceptibility to Infection Is Proportional to Target Cell Availability at Mucosal Sites

Cited by 70 publications

References 80 publications

Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

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