HIV-1–induced AIDS in monkeys

Hatziioannou, Théodora; Prete, Gregory Q. Del; Keele, Brandon F.; Estes, Jacob D.; McNatt, Matthew W.; Bitzegeio, Julia; Raymond, Alice; Rodriguez, Anthony B.; Schmidt, Fabian; Trubey, Charles M.; Smedley, Jeremy; Piatak, Michael; KewalRamani, Vineet N.; Lifson, Jeffrey D.; Bieniasz, Paul D.

doi:10.1126/science.1250761

Cited by 73 publications

(104 citation statements)

References 30 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…Although the A204E and G312V mutations were identified by adapting a SHIV encoding a single HIV-1 Env variant (Q23.17), the mutations increased mCD4-mediated entry and replication for HIV-1 Env proteins representing globally circulating HIV-1 variants of diverse subtypes (17,18). The G312V mutation was also observed in minimally modified HIV-1 passaged in macaques (19). In the present study, we assessed the conformational changes induced during adaptation to mCD4 across seven HIV-1 Env variants, including six cloned directly from the infected individual and several representing transmitted variants.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mutations in HIV-1 Envelope That Enhance Entry with the Macaque CD4 Receptor Alter Antibody Recognition by Disrupting Quaternary Interactions within the Trimer

Boyd

Peterson

Haggarty

et al. 2015

J Virol

View full text Add to dashboard Cite

Chimeric simian immunodeficiency virus (SIV)/human immunodeficiency virus (HIV) (SHIV) infection of macaques is commonly used to model HIV type 1 (HIV-1) transmission and pathogenesis in humans.Despite the fact that SHIVs encode SIV antagonists of the known macaque host restriction factors, these viruses require additional adaptation for replication in macaques to establish a persistent infection. Additional adaptation may be required in part because macaque CD4 (mCD4) is a suboptimal receptor for most HIV-1 envelope glycoprotein (Env) variants. This requirement raises the possibility that adaptation of HIV-1 Env to the macaque host leads to selection of variants that lack important biological and antigenic properties of the viruses responsible for the HIV-1 pandemic in humans. Here, we investigated whether this adaptation process leads to changes in the antigenicity and structure of HIV-1 Env. For this purpose, we examined how two independent mutations that enhance mCD4-mediated entry, A204E and G312V, impact antibody recognition in the context of seven different parental HIV-1 Env proteins from diverse subtypes. We also examined HIV-1 Env variants from three SHIVs that had been adapted for increased replication in macaques. Our results indicate that these different macaque-adapted variants had features in common, including resistance to antibodies directed to quaternary epitopes and sensitivity to antibodies directed to epitopes in the variable domains (V2 and V3) that are buried in the parental, unadapted Env proteins. Collectively, these findings suggest that adaptation to mCD4 results in conformational changes that expose epitopes in the variable domains and disrupt quaternary epitopes in the native Env trimer. IMPORTANCEThese findings indicate the antigenic consequences of adapting HIV-1 Env to mCD4. They also suggest that to best mimic HIV-1 infection in humans when using the SHIV/macaque model, HIV-1 Env proteins should be identified that use mCD4 as a functional receptor and preserve quaternary epitopes characteristic of HIV-1 Env. Macaque models of human immunodeficiency virus HIV type 1 (HIV-1) infection have been critical to preclinical vaccine and passive-immunization studies and to the understanding of HIV-1 pathogenesis. HIV-1 does not persistently infect macaques because of several species-specific host factors that prevent infection or inhibit viral replication (1). Simian immunodeficiency virus (SIV)/HIV chimeric viruses (SHIVs) encode SIV antagonists of these macaque restriction factors, and such SHIVs serve as surrogates of HIV-1 infection in macaques. Despite the fact that SHIVs incorporate the critical SIV antagonists of known macaque restriction factors, they require additional passage in vivo in order to replicate to high levels and cause persistent infection in macaques (1). Even with the improved understanding of host-virus interactions, there has been variable success in generating SHIVs capable of establishing infection in macaques, and this process remains expensive and labo...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Interestingly, these two mutations occur outside the CD4 binding site (CD4bs), in the C2 region (A204E) and the V3 loop (G312V) of the gp120 subunit of Env. A SHIV carrying the G312V change has also been selected in macaques (19).…”

mentioning

confidence: 99%

Mutations in HIV-1 Envelope That Enhance Entry with the Macaque CD4 Receptor Alter Antibody Recognition by Disrupting Quaternary Interactions within the Trimer

Boyd

Peterson

Haggarty

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…By way of comparison, the study of restriction factors (e.g. intrinsic immunity) has provided striking examples of cross-species barriers to transmission [70], while the study of the adaptive immunity in HIV infection has provided remarkable insights in the immune control of HIV-1 in patients [71]. Adaptive immune responses are tractable in patients thanks to the persistence of T and B cell response through antigenspecific cellular expansion and memory.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Innate immune sensing of HIV infection

Silvin¹,

Manel²

2015

Current Opinion in Immunology

View full text Add to dashboard Cite

“…Recently, by passaging HIV in vivo, researchers have obtained an HIV-1 strain with the ability to induce AIDS in pigtail macaques after transient depletion of CD8 ? T cells [18]. Although these pathogenic SHIVs have been commonly used, the pathogenic potential of the attenuated parental virus is not well understood.…”

Section: Discussionmentioning

confidence: 99%

High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques

Tian

Zhang

et al. 2015

Arch Virol

View full text Add to dashboard Cite

Chinese rhesus macaques (CRMs) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and for vaccine research. SHIV89.6 has been reported to be an attenuated virus because, in most cases, SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability of SHIV89.6 is not well understood. In this study, we found that 6 of 14 SHIV89.6-infected CRMs died within 127 weeks after infection. We found especially high immune activation, low IFN-α expression, and distinctive cytokine expression profiles in the infected and dead (ID) group of monkeys, while there was only few change in the CD4(+) T counts and distribution of T cell subsets in the ID group monkeys. Also, there was a similar dynamic of viral load between infected and surviving (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-α expression, and frequencies of cytokine-secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential in CRMs and that high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected CRMs. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be good predictors for disease progression and markers for therapy.

show abstract

HIV-1–induced AIDS in monkeys

Cited by 73 publications

References 30 publications

Mutations in HIV-1 Envelope That Enhance Entry with the Macaque CD4 Receptor Alter Antibody Recognition by Disrupting Quaternary Interactions within the Trimer

Mutations in HIV-1 Envelope That Enhance Entry with the Macaque CD4 Receptor Alter Antibody Recognition by Disrupting Quaternary Interactions within the Trimer

Innate immune sensing of HIV infection

High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques

Contact Info

Product

Resources

About